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151. Updates in adjuvant systemic therapy for melanoma

Author

Paul J. Mosca, April K.S. Salama, Brent A. Hanks, Craig L. Slingluff, Norma E. Farrow, Georgia M. Beasley, and Minyoung Kwak

Subjects
Oncology, Surgical resection, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, 030230 surgery, Systemic therapy, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Adjuvant therapy, Humans, Melanoma, Treatment regimen, business.industry, Disease Management, General Medicine, medicine.disease, Prognosis, Immune therapy, Clinical trial, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Surgery, Immunotherapy, business, Adjuvant
Abstract

There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.

Published
2018

152. Defining the effects of age and gender on immune response and outcomes to melanoma vaccination: a retrospective analysis of a single-institution clinical trials’ experience

Author

Nolan A. Wages, Mark E. Smolkin, Adriana G. Ramirez, Yinin Hu, and Craig L. Slingluff

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Multivariate analysis, Immunology, Adaptive Immunity, Cancer Vaccines, Article, Disease-Free Survival, Sex Factors, Internal medicine, medicine, Humans, Immunology and Allergy, Cumulative incidence, Melanoma, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Age Factors, Cancer, Retrospective cohort study, Middle Aged, medicine.disease, Clinical trial, Vaccination, Treatment Outcome, Multivariate Analysis, Vaccines, Subunit, Female, Cancer vaccine, business, CD8
Abstract

The impacts of patient age and gender on immune response (IR) and clinical outcome after cancer vaccines are not known. We hypothesized younger and female patients would have higher IR rates and better survival.Patients with resected stage IIB-IV melanoma in three clinical trials (Mel43, Mel44, Mel48) were vaccinated with 12 melanoma-associated peptides restricted by class I MHC. The cumulative incidence rate of CD8(+) T cell responses (direct interferon-gamma ELIspot assay) by week 7 was compared by age and gender. Overall survival (OS) and disease-free survival (DFS) landmark analyses were compared by Kaplan-Meier estimates and in multivariate analyses.T cell responses were evaluated in 327 patients and detected in 50 % of males and 48 % of females, with no difference in IR by gender or menopausal status. Males had trends toward longer DFS (p = 0.12) and OS (p = 0.09). Cumulative incidence of IR was higher in patients64 years of age versus older patients (p = 0.03). OS and DFS were similar by age group (p0.50). In multivariate modeling, younger age was associated with better IR (OR 0.40, p value 0.003), without an impact of age or gender on clinical outcomes.These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age/64 years.

Published
2015

153. Long-term Outcomes of Helper Peptide Vaccination for Metastatic Melanoma

Author

Yinin Hu, Christopher M. Blackwell, Helen Kim, and Craig L. Slingluff

Subjects
Adult, Male, Skin Neoplasms, Time Factors, T cell, Kaplan-Meier Estimate, Cancer Vaccines, Risk Assessment, Disease-Free Survival, Article, Sex Factors, Immune system, Antigen, Reference Values, medicine, Humans, Neoplasm Invasiveness, Prospective Studies, Neoplasm Metastasis, Melanoma, Survival analysis, Aged, Neoplasm Staging, Proportional Hazards Models, biology, business.industry, Immunogenicity, Vaccination, Age Factors, T-Lymphocytes, Helper-Inducer, Middle Aged, medicine.disease, Survival Analysis, United States, medicine.anatomical_structure, Immunology, biology.protein, Female, Surgery, Antibody, business, Follow-Up Studies
Abstract

Each year, over 70,000 Americans develop invasive melanoma, and roughly 9000 die with distant metastases.1 Overall survival for stage IV melanoma is poor, with one-year survival of 33-62% and median survival of 8-9 months.2 One in three patients undergo therapeutic metastasectomy,3 yet median survival after complete resection is only 2 to 4 years.4-7 New checkpoint blockade antibodies (to CTLA-4 or PD-1) and targeted therapies (inhibitors of mutated BRAF and MEK) promise to extend median survival of patients with stage IV melanoma. However, clinical responses with BRAF/MEK inhibition are usually transient,8 and although antibodies to CTLA-4 or PD-1 may produce more durable regressions, about 80% of treated patients still die of their disease within 5 years.9, 10 Thus, there is an urgent need for more effective treatment of advanced melanoma. Cancer vaccines offer promise to augment specific antitumor immunity and to improve clinical outcomes, despite negative results in most phase III trials to date.11-16 In preclinical models, vaccines against cancer antigens can induce strong T cell responses and can be therapeutic alone or in combination with other immune therapies.17, 18 However, vaccine approaches in humans are not optimized, and there is no consensus regarding the best way to induce therapeutic immune responses. Many vaccines have been developed to induce CD8+ T cells, but there has been limited focus on vaccines targeting CD4+ helper T cells. We have previously reported the safety, immunogenicity, and clinical activity of a combination vaccine comprised of 6 HLA-DR restricted peptides that can be recognized by helper T cells (6 melanoma helper peptides, 6MHP).19-21 Within these studies, cytokine profiles in peripheral blood and sentinel immunized nodes of vaccinated patients indicate a Th1-biased CD4+ T-cell immune response. Moreover, the proportion of FoxP3-positive T-cells responding to 6MHP does not increase with vaccination. The 6MHP vaccine can also induce a CD8+ T cell response through epitope spreading. In a multicenter trial incorporating 6MHP vaccines administered to patients with measurable stage IV melanoma, there was a significant association between the development of specific immune responses to 6MHP and overall survival; furthermore, 1 year survival compared favorably to prior experience.22, 23 We now have the opportunity to evaluate long-term outcomes of stage IV patients vaccinated with 6MHP on two clinical trials, and to test whether the association observed between immune response and survival in the E1602 trial is reproducible in another patient population. We hypothesized that vaccination with 6MHP would be associated with better overall survival than in untreated control patients, and that helper T cell immune responses to vaccination would be associated with improved overall survival.

Published
2015

154. Vaccines, Adjuvants, and Dendritic Cell Activators—Current Status and Future Challenges

Author

Joseph M. Obeid, Craig L. Slingluff, and Yinin Hu

Subjects
Oncology, medicine.medical_specialty, Cancer Vaccines, Article, Prostate cancer, Immune system, Adjuvants, Immunologic, Antigen, Neoplasms, Internal medicine, Humans, Medicine, business.industry, Immunotherapy, Active, Cancer, Dendritic Cells, Hematology, Dendritic cell, medicine.disease, Vaccine therapy, Current practice, Immunology, Cancer vaccine, Neoplasm Recurrence, Local, business
Abstract

Cancer vaccines offer a low-toxicity approach to induce anticancer immune responses. They have shown promise for clinical benefit with one cancer vaccine approved in the United States for advanced prostate cancer. As other immune therapies are now clearly effective for treatment of advanced cancers of many histologies, there is renewed enthusiasm for optimizing cancer vaccines for use to prevent recurrence in early-stage cancers and/or to combine with other immune therapies for therapy of advanced cancers. Future advancements in vaccine therapy will involve the identification and selection of effective antigen formulations, optimization of adjuvants, dendritic cell (DC) activation, and combination therapies. In this summary we present the current practice, the broad collection of challenges, and the promising future directions of vaccine therapy for cancer.

Published
2015

155. TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10

Author

Craig L. Slingluff, Yongde Bao, Donna H. Deacon, Walter C. Olson, Ileana S. Mauldin, and Ena Wang

Subjects
Cancer Research, Toll-like receptor, Chemokine, Tumor microenvironment, Melanoma, Biology, medicine.disease, TLR2, Immune system, Oncology, Immunology, medicine, biology.protein, CXCL10, Interferon gamma, medicine.drug
Abstract

Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cell infiltration of metastases. However, most tumors lack significant immune infiltration prior to therapy. Selected chemokines promote T-cell migration into tumors; thus, agents that induce these chemokines in the tumor microenvironment (TME) may improve responses to systemic immune therapy. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the TME. Here, we show that toll-like receptor (TLR) agonists can induce chemokine production directly from melanoma cells when combined with IFNγ treatment. We find that TLR2 and TLR6 are widely expressed on human melanoma cells, and that TLR2/6 agonists (MALP-2 or FSL-1) synergize with interferon-gamma (IFNγ) to induce production of CXCL10 from melanoma cells. Furthermore, melanoma cells and immune cells from surgical specimens also respond to TLR2/6 agonists and IFNγ by upregulating CXCL10 production, compared to treatment with either agent alone. Collectively, these data identify a novel mechanism for inducing CXCL10 production directly from melanoma cells, with TLR2/6 agonists +IFNγ and raise the possibility that intratumoral administration of these agents may improve immune signatures in melanoma and have value in combination with other immune therapies, by supporting T-cell migration into melanoma metastases.

Published
2015

156. Utility of sentinel lymph node biopsy for solitary dermal melanomas

Author

Craig L. Slingluff, Puja Shah, Yinin Hu, and MA George J. Stukenborg PhD

Subjects
medicine.medical_specialty, medicine.diagnostic_test, Cost effectiveness, business.industry, Wide local excision, medicine.medical_treatment, Melanoma, Sentinel lymph node, Cancer, General Medicine, Sentinel node, medicine.disease, Surgery, Oncology, Biopsy, medicine, business, Survival rate
Abstract

Background and Objectives Solitary dermal melanoma (SDM) is melanoma confined to subcutaneous and/or dermal layers in the absence of a known primary cutaneous lesion. We hypothesized that sentinel node biopsy is an effective staging strategy for this rare disease. Methods A Markov decision model was constructed to represent two management strategies for SDM: wide local excision followed by observation, and wide local excision followed by sentinel node biopsy. Utilities, likelihood of positive sentinel node biopsy, and cancer progression rates during a five year time horizon were assigned based on institutional data and a review of existing literature. Estimated costs were derived using Medicare reimbursements. Results Excision followed by sentinel node biopsy provides greater utility, yielding 3.85 discounted quality-adjusted life years (dQALY) compared to 3.66 for excision alone. The incremental cost-effectiveness ratio for sentinel node biopsy is $19,102 per dQALY. Sensitivity analyzes demonstrated that observation is more cost-effective if greater than 23% of sentinel node biopsies are positive (16% reported), or if 5-year survival for observed patients is greater than 76% (69% reported). Conclusions Based on existing clinical evidence, sentinel node biopsy yields greater utility than excision alone and is cost-effective for patients presenting with solitary dermal melanoma. J. Surg. Oncol. 2015 111:800–807. © 2014 Wiley Periodicals, Inc.

Published
2015

157. Total body photography for skin cancer screening

Author

Anneke T. Schroen, Scott T. Acton, Gina R. Petroni, David Chen, Joshua M. Judge, Craig L. Slingluff, and Lynn T. Dengel

Subjects
Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Time Factors, Attitude of Health Personnel, Pilot Projects, Image processing, Dermatology, Sensitivity and Specificity, Article, Image Processing, Computer-Assisted, Photography, Humans, Medicine, Melanoma, Early Detection of Cancer, Skin cancer screening, business.industry, Total body, Image capture, Visualization, Patient Satisfaction, Feasibility Studies, Female, Radiology, Pigmented skin, business, Software, Total body photography
Abstract

Background Total body photography may aid in melanoma screening but is not widely applied due to time and cost. We hypothesized that a near-simultaneous automated skin photo-acquisition system would be acceptable to patients and could rapidly obtain total body images that enable visualization of pigmented skin lesions. Methods From February to May 2009, a study of 20 volunteers was performed at the University of Virginia to test a prototype 16-camera imaging booth built by the research team and to guide development of special purpose software. For each participant, images were obtained before and after marking 10 lesions (five “easy” and five “difficult”), and images were evaluated to estimate visualization rates. Imaging logistical challenges were scored by the operator, and participant opinion was assessed by questionnaire. Results Average time for image capture was three minutes (range 2–5). All 55 “easy” lesions were visualized (sensitivity 100%, 90% CI 95–100%), and 54/55 “difficult” lesions were visualized (sensitivity 98%, 90% CI 92–100%). Operators and patients graded the imaging process favorably, with challenges identified regarding lighting and positioning. Conclusions Rapid-acquisition automated skin photography is feasible with a low-cost system, with excellent lesion visualization and participant acceptance. These data provide a basis for employing this method in clinical melanoma screening.

Published
2014

158. Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8

Author

Timothy N. J. Bullock, Kyle L. Hoehn, Peter J. Siska, Craig L. Slingluff, Jeffrey C. Rathmell, Xiaojing Liu, Jason W. Locasale, Hideo Yagita, Xia Gao, Marin E. Nelson, and Lelisa Gemta

Subjects
0301 basic medicine, T cell, Immunology, Enolase, Programmed Cell Death 1 Receptor, Context (language use), chemical and pharmacologic phenomena, Oxidative phosphorylation, CD8-Positive T-Lymphocytes, Immunotherapy, Adoptive, Article, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, medicine, Cytotoxic T cell, Animals, Humans, Glycolysis, Hepatitis A Virus Cellular Receptor 2, Melanoma, Glucose Transporter Type 1, Chemistry, Effector, hemic and immune systems, General Medicine, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Glucose, 030220 oncology & carcinogenesis, Immunoglobulin G, Phosphopyruvate Hydratase, Cancer research, CD8
Abstract

In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8+ TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8+ melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8+ TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8+ TILs. We found high expression of both enolase 1 mRNA and protein in CD8+ TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8+ TIL dysfunction.

Published
2017

159. Vaccine-draining lymph nodes of cancer patients for generating anti-cancer antibodies

Author

Chelsea L. Carman, Walter C. Olson, Stephanie C. Pero, Yu-Jing Sun, Craig L. Slingluff, David N. Krag, and Girja S. Shukla

Subjects
0301 basic medicine, Enzyme-Linked Immunospot Assay, Antibodies, Neoplasm, CD40 Ligand, lcsh:Medicine, Cancer Vaccines, Antibodies, General Biochemistry, Genetics and Molecular Biology, Melanoma Vaccine, 03 medical and health sciences, 0302 clinical medicine, Cancer vaccine, medicine, Humans, Melanoma, Lymph node, B cell, B-Lymphocytes, B cells, Hybridomas, CD40, biology, business.industry, Research, lcsh:R, General Medicine, Flow Cytometry, medicine.disease, Clone Cells, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Immunoglobulin G, 030220 oncology & carcinogenesis, Immunology, biology.protein, Lymph Nodes, Lymph, Antibody, Peptides, business, Protein Binding, Human
Abstract

Background Our research is focused on using the vaccine draining lymph node to better understand the immune response to cancer vaccines and as a possible source of anti-cancer reagents. We evaluated vaccine draining lymph nodes archived from a clinical study in melanoma patients and determined the reaction of B cells to the vaccine peptides. Methods Mononuclear cells (MNCs) were recovered from cryopreserved lymph nodes that were directly receiving drainage from multi-peptide melanoma vaccine. The patients were enrolled on a vaccine study (NCT00089219, FDA, BB-IND No. 10825). B cell responses in the vaccine-draining lymph nodes were studied under both stimulated and un-stimulated conditions. Cryopreserved cells were stimulated with CD40L, stained with multiple human cell-surface markers (CD19, CD27, IgM) to identify different categories of B cell sub populations with flow cytometry. Hybridomas were generated from the lymph node cells after CD40L-stimulation. Cells were fused to murine plasmacytoma P3X63.Ag8.653 using Helix electrofusion chamber. ELISA was used to evaluate hybridoma derived antibody binding to vaccine peptides. Results Viable MNCs were satisfactorily recovered from lymph nodes cryopreserved from six vaccine study patients 8–14 years previously. B cell ELISPOT demonstrated responses for each patient to multiple vaccine peptides. CD40L stimulation of lymph node cells increased the proportion of CD19+ CD27+ cells from 12 to 65% of the sample and increased the proportion of class-switched cells. Screening of IgG secreting clones demonstrated binding to melanoma vaccine peptides. Conclusions B cells were successfully recovered and expanded from human cryopreserved vaccine-draining lymph nodes. Individual B cells were identified that secreted antibodies that bound to cancer vaccine peptides. The ability to reliably generate in vitro the same antibodies observed in the blood of vaccinated patients will facilitate research to understand mechanisms of human antibody activity and possibly lead to therapeutic antibodies.

Published
2017

160. Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test

Author

Kelly M. McMasters, Kyle R. Covington, Jeffrey J. Sussman, Eddy C. Hsueh, Robert W. Cook, Craig L. Slingluff, James R. DeBloom, Clare Johnson, Jonathan Lee, and Brooke Middlebrook

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Staging, lcsh:RC254-282, Metastasis, Breslow Thickness, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Prospective cohort study, Molecular Biology, Survival rate, lcsh:RC633-647.5, Proportional hazards model, business.industry, Melanoma, Research, lcsh:Diseases of the blood and blood-forming organs, Hematology, DecisionDx-Melanoma, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Interim analysis, Prognosis, Gene expression profiling, 030220 oncology & carcinogenesis, Cohort, business, Cutaneous melanoma, Cohort study
Abstract

Background A 31-gene expression profile (GEP) test that provides risk classification of cutaneous melanoma (CM) patients has been validated in several retrospective studies. The objective of the reported study was a prospective evaluation of the GEP performance in patients enrolled in two clinical registries. Methods Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age ≥ 16 years, successful GEP result and ≥1 follow-up visit for inclusion in this interim analysis. Primary endpoints were recurrence-free (RFS), distant metastasis-free (DMFS), and overall survival (OS). Results Median follow-up was 1.5 years for event-free patients. Median age for subjects was 58 years (range 18–87) and median Breslow thickness was 1.2 mm (range 0.2–12.0). Eighty-eight percent (282/322) of cases had stage I/II disease and 74% (237/322) had a SLN biopsy. Seventy-seven percent (248/322) had class 1 molecular profiles. 1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p

Published
2017

161. Evaluation of SAS1B as a target for antibody-drug conjugate therapy in the treatment of pancreatic cancer

Author

Sara J. Adair, Todd W. Bauer, Arabinda Mandal, Kiley A. Knapp, Anne M. Mills, Craig L. Slingluff, John C. Herr, J. Thomas Parsons, Timothy N. J. Bullock, Walter C. Olson, and Eusebio S. Pires

Subjects
0301 basic medicine, Cellular immunity, Antibody-drug conjugate, Antibody-Drug Conjugate Therapy, medicine.drug_class, Cell, Monoclonal antibody, antibody-drug conjugate, 03 medical and health sciences, 0302 clinical medicine, Antigen, Immunotoxin, Pancreatic cancer, Medicine, business.industry, ASTL/SAS1B/ovastacin, surface cancer-oocyte antigen, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, pancreatic cancer biomarker, Cancer research, targeted immunotherapy, business, Research Paper
Abstract

Successful therapeutic options remain elusive for pancreatic cancer. The exquisite sensitivity and specificity of humoral and cellular immunity may provide therapeutic approaches if antigens specific for pancreatic cancer cells can be identified. Here we characterize SAS1B (ovastacin, ASTL, astacin-like), a cancer-oocyte antigen, as an attractive immunotoxin target expressed at the surface of human pancreatic cancer cells, with limited expression among normal tissues. Immunohistochemistry shows that most pancreatic cancers are SAS1Bpos (68%), while normal pancreatic ductal epithelium is SAS1Bneg. Pancreatic cancer cell lines developed from patient-derived xenograft models display SAS1B cell surface localization, in addition to cytoplasmic expression, suggesting utility for SAS1B in multiple immunotherapeutic approaches. When pancreatic cancer cells were treated with an anti-SAS1B antibody-drug conjugate, significant cell death was observed at 0.01-0.1 μg/mL, while SAS1Bneg human keratinocytes were resistant. Cytotoxicity was correlated with SAS1B cell surface expression; substantial killing was observed for tumors with low steady state SAS1B expression, suggesting a substantial proportion of SAS1Bpos tumors can be targeted in this manner. These results demonstrate SAS1B is a surface target in pancreatic cancer cells capable of binding monoclonal antibodies, internalization, and delivering cytotoxic drug payloads, supporting further development of SAS1B as a novel target for pancreatic cancer.

Published
2017

162. Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study

Author

Randall P. Scheri, J. Harrison Howard, April K.S. Salama, Linda M. Youngwirth, Syed Gardezi, Douglas S. Tyler, Yinin Hu, Craig L. Slingluff, Doreen M. Agnese, Alicia M. Terando, Georgia M. Beasley, and Kara K. Rossfeld

Subjects
medicine.medical_specialty, Skin Neoplasms, Sentinel lymph node, Population, Disease-Free Survival, Article, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Biopsy, medicine, Humans, 030212 general & internal medicine, education, Survival rate, Lymph node, Melanoma, Retrospective Studies, education.field_of_study, medicine.diagnostic_test, business.industry, Sentinel Lymph Node Biopsy, Retrospective cohort study, medicine.disease, Neoplastic Cells, Circulating, Surgery, Survival Rate, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Disease Progression, Lymph Node Excision, Neoplasm Recurrence, Local, Sentinel Lymph Node, business, Lymphoscintigraphy
Abstract

BACKGROUND. Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma. METHODS. Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population. RESULTS. The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5-50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75–2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7–10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06). CONCLUSION. SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

Published
2017

163. Peptide Vaccine: Overview

Author

Craig L. Slingluff and Patrick M. Dillon

Subjects
03 medical and health sciences, 0302 clinical medicine, business.industry, 030220 oncology & carcinogenesis, Peptide vaccine, Medicine, business, Virology, 030215 immunology
Published
2017

164. Immunolabeling for p16, WT1, and Fli-1 in the Assignment of Growth Phase for Cutaneous Melanomas

Author

Allen G. Strickler, Jochen T. Schaefer, Craig L. Slingluff, and Mark R. Wick

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Radial Growth Phase, Dermatology, Pathology and Forensic Medicine, Young Adult, Immunolabeling, Biomarkers, Tumor, medicine, Vertical Growth Phase, Humans, WT1 Proteins, Melanoma, Cyclin-Dependent Kinase Inhibitor p16, biology, Proto-Oncogene Protein c-fli-1, fungi, General Medicine, Middle Aged, medicine.disease, Immunohistochemistry, Neoplasm Proteins, Staining, biology.protein, Female, Antibody, Immunostaining
Abstract

Distinction between radial growth phase (RGP) and vertical growth phase (VGP) in cutaneous melanomas is prognostically significant. Despite established morphological criteria, molecular markers to separate RGP and VGP have not been well established. The goal of this study was to investigate associations of p16, WT1, and Fli-1 with RGP-to-VGP progression, by immunohistochemistry. The p16 is a tumor suppressor, whereas WT1 and Fli-1 are transcriptional activators. The authors hypothesized that entry into VGP would be associated with decreased p16 and increased WT1 and Fli-1. Paraffin sections from 18 RGP and 15 VGP melanomas were immunostained with well-characterized antibodies to p16, WT1, and Fli-1. Melanoma growth phases were determined using precodified morphological attributes. In RGP melanomas, p16 was expressed in 15 of 18 (83%), WT1 in 17 of 17 (100%), and Fli-1 at least focally in 6 of 18 (33%). The deep dermal component of VGP melanomas stained positively for Fli-1 in 9 of 14 (64%), strongly for WT1 in 10 of 14 (71%), and strongly for p16 in only 2 of 15 (13%). Observed patterns of WT1 immunopositivity did not support the authors' hypothesis; it is not likely to be a good indicator of VGP. On the other hand, Fli-1 staining trended toward more positive deep tumor compartment staining and p16 to weaker staining in the deep compartment. At present, application of histological criteria remains the best method for assignment of growth phase in melanomas; however, p16 and possibly Fli-1 immunostains may serve as useful adjuncts in morphologically indeterminate cases.

Published
2014

165. Inflammatory Adverse Events are Associated with Disease-Free Survival after Vaccine Therapy among Patients with Melanoma

Author

Gina R. Petroni, Emily J. White, Patrice Y. Neese, Yinin Hu, Mark E. Smolkin, and Craig L. Slingluff

Subjects
Adult, Lung Diseases, Male, Oncology, medicine.medical_specialty, Vitiligo, CD8-Positive T-Lymphocytes, Nodular melanoma, Skin Diseases, Article, Antigens, Neoplasm, Internal medicine, medicine, Humans, Adverse effect, Melanoma, Survival rate, Neoplasm Staging, Inflammation, business.industry, Histocompatibility Antigens Class I, Hazard ratio, Immunotherapy, Active, Common Terminology Criteria for Adverse Events, Middle Aged, Prognosis, medicine.disease, Survival Rate, Immunology, Female, Surgery, Neoplasm Recurrence, Local, business, CD8, Follow-Up Studies
Abstract

Multipeptide vaccines for melanoma may cause inflammatory adverse events (IAE). We hypothesize that IAE are associated with a higher rate of immune response (IR) to vaccination and improved clinical outcomes.Adult patients with resected, high-risk (stage IIB to IV) melanoma were vaccinated with a combination of 12 class I major histocompatibility complex (MHC)-restricted melanoma epitopes, and IAE were recorded. A separate category for hypopigmentation (vitiligo) was also assessed. CD8(+) T cell IR was assessed by direct interferon gamma ELISpot analysis. Overall survival and disease-free survival were analyzed by Cox proportional hazard modeling.Out of 332 patients, 57 developed IAE, the majority of which were dermatologic (minimum Common Terminology Criteria for Adverse Events [CTCAE] grade 3). Most nondermatologic IAE were CTCAE grade 1 and 2. Vitiligo developed in 23 patients (7 %). A total of 174 patients (53 %) developed a CD8(+) response. Presence of IAE was significantly associated with development of IR (70 vs. 49 %, p = 0.005) and with disease-free survival (hazard ratio 0.54, p = 0.043). There were no significant associations relating vitiligo or IR alone with clinical outcomes.IAE are associated with a higher rate of CD8(+) T cell response after vaccination therapy for high-risk melanoma. Our findings suggest either that antitumor activity induced by class I MHC-restricted peptide vaccines may depend on immunologic effects beyond simple expansion of CD8(+) T cells or that the intrinsic inflammatory response of patients contributes to clinical outcome in melanoma.

Published
2014

166. Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine

Author

William W. Grosh, Andrea Czarkowski, Mark E. Smolkin, Walter C. Olson, Gina R. Petroni, Craig L. Slingluff, Yinin Hu, and Kimberly A. Chianese-Bullock

Subjects
Cancer Research, Skin Neoplasms, T cell, Molecular Sequence Data, Immunology, Human leukocyte antigen, Major histocompatibility complex, Cancer Vaccines, Article, Epitope, Epitopes, HLA Antigens, MHC class I, Humans, Immunology and Allergy, Medicine, Amino Acid Sequence, Melanoma, Alleles, biology, business.industry, Immunogenicity, Cell Differentiation, Virology, medicine.anatomical_structure, Oncology, CD4 Antigens, Melanoma Helper Peptide Vaccine, biology.protein, Peptides, business, CD8
Abstract

Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4(+) and CD8(+) T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-γ ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4(+) T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE-A3281-295 (49 %) and tyrosinase386-406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8(+) T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4(+) and CD8(+) T cell responses against melanoma antigens. CD4(+) T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8(+) T cell responses suggests epitope spreading and systemic activity mediated at the tumor site.

Published
2014

167. Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature

Author

Paul R. Kunk, Craig L. Slingluff, Alejandro A. Gru, Anne M. Stowman, Elizabeth Gaughan, and Joshua E. Reuss

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Metastatic melanoma, Sarcoidosis, medicine.medical_treatment, Immunology, Combination immunotherapy, Ipilimumab, Case Report, 03 medical and health sciences, 0302 clinical medicine, Checkpoint inhibitor, Biopsy, Immune-related adverse event, Immunology and Allergy, Medicine, 030212 general & internal medicine, Histiocyte, Pharmacology, medicine.diagnostic_test, business.industry, Melanoma, Immunotherapy, medicine.disease, Dermatology, Nivolumab, Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, business, medicine.drug
Abstract

Background We report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity. Case presentation A 46 year old Caucasian female with M1c-metastatic melanoma was managed with ipilimumab/nivolumab combination. Patient experienced response in baseline lesions but developed new clinical and radiographic findings. Biopsy of new lesions at two different sites both demonstrated tumefactive sarcoidosis. Staining of the biopsy tissue for PD-L1 expression demonstrated strong PD-L1 staining of the histiocytes and lymphocytes within the granulomas. Monotherapy nivolumab was continued without progression of sarcoid findings or clinical deterioration. Conclusions Tissue biopsy for evaluation of new lesions on immunotherapy is an important step to help guide decision making, as non-melanoma lesions can mimic disease progression.

Published
2016

168. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016

169. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016

170. Correction to: Characteristics Associated with Pathologic Nodal Burden in Patients Presenting with Clinical Melanoma Nodal Metastasis

Author

Georgia M. Beasley, Giorgos C. Karakousis, Norma E. Farrow, Andrew D. Tieniber, Jonathan G. Davick, Phyllis A. Gimotty, Yun Song, Craig L. Slingluff, Minyoung Kwak, and Gabriella N. Tortorello

Subjects
medicine.medical_specialty, business.industry, Melanoma, Nodal metastasis, MEDLINE, medicine.disease, Oncology, Surgical oncology, Medicine, Surgery, In patient, Radiology, business, NODAL
Abstract

In the original article, there is an error in the funding information. The correct funding information is as follows.

Published
2019

171. T cells in the human metastatic melanoma microenvironment express site-specific homing receptors and retention integrins

Author

Elise P. Salerno, Craig L. Slingluff, Walter C. Olson, Chantel McSkimming, and Sofia M. Shea

Subjects
Cancer Research, Tumor microenvironment, Pathology, medicine.medical_specialty, biology, Melanoma, Integrin, CXCR3, medicine.disease, Chemokine receptor, medicine.anatomical_structure, Oncology, biology.protein, medicine, Lymph node, Homing (hematopoietic), Cancer immunology
Abstract

T-cell infiltration into the metastatic melanoma microenvironment (MME) correlates with improved patient survival. However, diffuse infiltration into tumor occurs in only 8% of melanoma metastases. Little is known about mechanisms governing T-cell infiltration into human melanoma metastases or about how those mechanisms may be altered therapeutically. We hypothesized that T cells in the MME would be enriched for chemokine receptors CCR4, CCR5, CXCR3 and homing receptors relevant to the tissue site. Viably cryopreserved single cell suspensions from nineteen melanoma metastases representing three metastatic sites (tumor-infiltrated lymph node, skin and small bowel) were evaluated by multiparameter flow cytometry and compared to benign lymph nodes and peripheral blood mononuclear cells from patients with Stage IIB-IV melanoma. T cells in the melanoma metastases contained large effector memory populations, high proportions of activated, moderately differentiated cells and few regulatory T cells. Site-specific homing was suggested in bowel, with high expression of CCR9. We neither encounter the anticipated enrichment of integrin α4β7 in bowel, cutaneous leukocyte antigen (CLA) in skin, nor integrin α4β1 or receptor CXCR3 in metastatic sites. Retention integrins αEβ7, α1β1 and α2β1 were significantly elevated in metastases. These data suggest limited tissue site-specific homing to human melanoma metastases, but a significant role for retention integrins in maintaining intratumoral T cells. Our findings also raise the possibility that T-cell homing, infiltration, and retention in melanoma metastases may be increased by increasing expression of ligands for CLA, α4β1 and CXCR3 on intratumoral endothelium.

Published
2013

172. Evaluating Nelipepimut-S in the Treatment of Breast Cancer: A Short Report on the Emerging Data.

Author

Dillon, Patrick M, Brenin, Christiana M, and Jr, Craig L Slingluff

Subjects
BREAST cancer, CANCER treatment, CANCER vaccines, CANCER prevention, VACCINES
Abstract

Vaccine therapies for treatment and prevention of cancer have seen modest degrees of efficacy with wide variation related to the tumor type, vaccine type, adjuvants and clinical setting for their study. Over the course of the last two decades, various peptide vaccines for breast cancer have been studied. The current leading peptide vaccine for human application is a HER2-based vaccine known as Nelipepimut-S, which has demonstrated immune activity and promising clinical activity in some settings. This review covers the development of this newer peptide vaccine for both HER2 amplified and non-amplified breast cancer. [ABSTRACT FROM AUTHOR]

Published
2020
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173. Design, Development, and Evaluation of a Novel Retraction Device for Gallbladder Extraction During Laparoscopic Cholecystectomy

Author

William F. Johnston, Peter T. Hallowell, George J. Stukenborg, William H. Guilford, Craig L. Slingluff, and Joshua M. Judge

Subjects
Laparoscopic surgery, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Gallstones, Article, Surgical Equipment, Port (medical), medicine, Humans, Surgical Wound Infection, Cholecystectomy, Laparoscopy, Pain, Postoperative, medicine.diagnostic_test, business.industry, General surgery, Gallbladder, Gastroenterology, Equipment Design, medicine.disease, Surgery, medicine.anatomical_structure, Abdomen, Laparoscopic Port, business
Abstract

A source of frustration during laparoscopic cholecystectomy involves extraction of the gallbladder through port sites smaller than the gallbladder itself. We describe the development and testing of a novel device for the safe, minimal enlargement of laparoscopic port sites to extract large, stone-filled gallbladders from the abdomen.The study device consists of a handle with a retraction tongue to shield the specimen and a guide for a scalpel to incise the fascia within the incision. Patients enrolled underwent laparoscopic cholecystectomy. Gallbladder extraction was attempted. If standard measures failed, the device was implemented. Extraction time and device utility scores were recorded for each patient. Patients returned 3-4 weeks postoperatively for assessment of pain level, cosmetic effect, and presence of infectious complications.Twenty (51 %) of 39 patients required the device. Average extraction time for the first eight patients was 120 s. After interim analysis, an improved device was used in 12 patients and average extraction time was 24 s. There were no adverse events. Postoperative pain ratings and incision cosmesis were comparable between patients with and without use of the device.The study device enables safe and rapid extraction of impacted gallbladders through the abdominal wall.

Published
2013

174. Clinical Activity and Safety of Combination Therapy with Temsirolimus and Bevacizumab for Advanced Melanoma: A Phase II Trial (CTEP 7190/Mel47)

Author

Cheryl Murphy Chase, Geoffrey R. Weiss, Kimberly A. Chianese-Bullock, William W. Grosh, Prahlad T. Ram, Gina R. Petroni, David L. Brautigan, Michael J. Weber, Alison Gaucher, Jeffrey E. Gershenwald, Sofia M. Shea, Anthony J. Olszanski, Gulsun Erdag, Aubrey G Wagenseller, Lainie P. Martin, Mark E. Smolkin, Kerrington R. Molhoek, Craig L. Slingluff, Amber L. Shada, and Walter C. Olson

Subjects
Adult, Male, Proto-Oncogene Proteins B-raf, Oncology, Cancer Research, medicine.medical_specialty, Combination therapy, Bevacizumab, Biopsy, Antibodies, Monoclonal, Humanized, Article, GTP Phosphohydrolases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Melanoma, Aged, Neoplasm Staging, Aged, 80 and over, Sirolimus, business.industry, Membrane Proteins, Middle Aged, Phosphoproteins, medicine.disease, Temsirolimus, Surgery, Clinical trial, Ki-67 Antigen, Treatment Outcome, Response Evaluation Criteria in Solid Tumors, Mutation, Female, business, Progressive disease, medicine.drug
Abstract

Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0–39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4+FoxP3+ cells. Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies. Clin Cancer Res; 19(13); 3611–20. ©2013 AACR.

Published
2013

175. Infrared thermography of cutaneous melanoma metastases

Author

Gina R. Petroni, Craig L. Slingluff, Lynn T. Dengel, Amber L. Shada, Scott T. Acton, and Mark E. Smolkin

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Skin Neoplasms, Infrared Rays, Diagnostico diferencial, Pilot Projects, Sensitivity and Specificity, Article, Metastasis, Diagnosis, Differential, Neoplasms, Biopsy, Humans, Medicine, Melanoma, neoplasms, Melanoma diagnosis, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, Thermography, Positron emission tomography, Cutaneous melanoma, Feasibility Studies, Female, Surgery, Patient Safety, business
Abstract

Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions.Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0-5,5-15,15-30, and30 mm. Images were scored on a scale from -1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored.IR imaging was able to determine the malignancy of small (0-5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions5-15 mm, sensitivity was 58% and specificity 98%. For lesions15-30 mm, sensitivity was 95% and specificity 100%, and for lesions30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%-100% across all strata, and the negative predictive value was 95% for15-30 mm lesions and 80% for30 mm lesions.Malignant lesions15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies.

Published
2013

176. A case of spontaneous systemic immunity to melanoma associated with cure after amputation for extensive regional recurrence

Author

William W. Grosh, Kelly T. Smith, Achim A. Jungbluth, Louis B. Brill, Joshua M. Judge, James W. Patterson, Donna H. Deacon, Sacha Gnjatic, and Craig L. Slingluff

Subjects
Cancer Research, medicine.medical_specialty, Skin Neoplasms, Time Factors, Palliative care, medicine.medical_treatment, Immunology, Systemic immunity, Tumor immunity, Amputation, Surgical, Article, Immune system, Antigens, Neoplasm, medicine, Humans, Immunology and Allergy, Lymphocytes, Survivors, Melanoma, Aged, biology, business.industry, Palliative Care, Membrane Proteins, medicine.disease, Surgery, Lower Extremity, Oncology, Amputation, biology.protein, Female, Neoplasm Recurrence, Local, NY-ESO-1, Antibody, business
Abstract

Survival after amputation for melanoma is short; however, rare long-term survivors are reported. The mechanism for durable systemic tumor control in patients with regional failure is not known. To explore whether systemic tumor immunity may be implicated, tumor and circulating immune responses were examined in a patient who survived disease-free 14 years after hip disarticulation.A 71-year-old female with extensive regional metastases of melanoma in the left lower extremity underwent amputation for palliative reasons. Tumor was collected at surgery, and blood was collected during follow-up. Tumor sections were evaluated for lymphocytic infiltration and NY-ESO-1 expression by immunohistochemistry. Cellular immune responses to defined tumor antigens were evaluated by ELISPOT assay, and antibody responses to a panel of tumor antigens were assayed by ELISA.The patient's tumor had minimal lymphocytic infiltrate (immunotype A). NY-ESO-1 was strongly expressed by the melanoma cells. Circulating T-cell responses to NY-ESO-1 peptides were observed 6 and 12 years postoperatively, and antibodies to NY-ESO-1 were detected 2-6 years after surgery.The patient described in this report experienced relentless regional tumor progression, with intravascular metastases, and then 14-year systemic disease-free survival after palliative resection, without evidence of melanoma recurrence before death from other causes. Her immune response to NY-ESO-1 likely failed to control established regional metastases because T cells were unable to infiltrate them. It is possible, however, that among other factors, the host immune response may have contributed to systemic protection.

Published
2013

177. Surgical Management of the Patient with Metastatic Melanoma to the Heart

Author

Joshua M. Judge, John A. Kern, Irving L. Kron, Geoffrey R. Weiss, John D. Tillou, and Craig L. Slingluff

Subjects
Pulmonary and Respiratory Medicine, Oncology, Difficult problem, medicine.medical_specialty, Metastatic melanoma, business.industry, Melanoma, Autopsy, medicine.disease, Surgery, Heart neoplasms, Internal medicine, cardiovascular system, Cardiac metastasis, medicine, Ultrasonography, Cardiology and Cardiovascular Medicine, business, Melanoma diagnosis
Abstract

Melanoma has a high propensity for cardiac seeding, with heart involvement noted in a significant number of patients at autopsy. Therapeutic options are currently limited, and the prognosis of cardiac metastasis is poor. We report two cases of cardiac metastasis of melanoma and review the current literature. In addition, we propose an algorithm for dealing with this difficult problem.

Published
2013

178. Research incentive program for clinical surgical faculty associated with increases in research productivity

Author

Florence E. Turrentine, Craig L. Slingluff, Monika J. Thielen, Irving L. Kron, and Anneke T. Schroen

Subjects
Pulmonary and Respiratory Medicine, Biomedical Research, Faculty, Medical, Time Factors, education, Awards and Prizes, MEDLINE, Efficiency, Efficiency, Organizational, Discount points, Hospitals, University, Academic department, Research Support as Topic, Surveys and Questionnaires, Humans, Speech, Medicine, Incentive program, Productivity, health care economics and organizations, Response rate (survey), Motivation, Medical education, Impact factor, business.industry, Virginia, Recognition, Psychology, Authorship, Incentive, Surgery, Journal Impact Factor, Periodicals as Topic, Cardiology and Cardiovascular Medicine, business, Program Evaluation
Abstract

Objective To develop a research productivity scoring program within an academic department of surgery that would help realign incentives to encourage and reward research. Although research is highly valued in the academic mission, financial incentives are generally aligned to reward clinical productivity. Methods A formula assigning points for publications and extramural grants was created and used to award a research incentive payment proportional to the research productivity score, beginning July 2007. Publication points reflect journal impact factor, author role, and manuscript type. Grant points reflect total funding and percentage of effort. Publication data were gathered from Web of Science/PubMed/Medline and grants data from the departmental grants office. An annual award is presented to the person with the greatest improvement. The research productivity score data after July 2007 were compared with control data for the 2 preceding years. A 33-question survey to 28 clinical faculty was conducted after the first year to measure satisfaction and solicit constructive feedback. Results The mean annual point scores increased from the preresearch productivity score to the postresearch productivity score academic years (2180 vs 3389, respectively, P = .08), with a significant change in the grant component score (272 vs 801, P = .03). Since research productivity score implementation, the operative case volumes increased 4.3% from 2006 to 2011. With a response rate of 89%, the survey indicated that 76% of the faculty wished to devote more time to research and 52% believed 1 or more research-related behaviors would change because of the research productivity score program. Conclusions An objective, transparent research incentive program, through both monetary incentives and recognition, can stimulate productivity and was well-received by faculty.

Published
2012

179. Heterogeneity of CD8

Author

Joseph M, Obeid, Nolan A, Wages, Yinin, Hu, Donna H, Deacon, and Craig L, Slingluff

Subjects
Lung Neoplasms, Lymphocytes, Tumor-Infiltrating, Carcinoma, Non-Small-Cell Lung, Humans, CD8-Positive T-Lymphocytes, Prognosis, Immunohistochemistry, Survival Analysis, Article
Abstract

Infiltration of non-small-cell lung cancer (NSCLC) by CD8Twenty-three primary NSCLC tumors were immunohistochemically stained for CD8 and were assessed using automated software with eight different sampling strategies or the whole tumor. Results of all sampling strategies were compared to the whole tumor counts (paired t tests, Pearson's r). Associations between CD8 densities and overall survival were assessed (log-rank test).Counts from all eight sampling strategies significantly correlated with whole tumor counts (p ≤ 0.001). However, the magnitude of CD8Different tumor sampling strategies may yield discordant TIL density results and different stratification for risk assessment. Small biopsies may be particularly unrepresentative. Random sampling of larger tumor areas is recommended. Enumerating CD8

Published
2016

180. Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors

Author

Elizabeth Gaughan, Paul R. Kunk, Patrick M. Dillon, R. Hall, Ryan D. Gentzler, Craig L. Slingluff, and Osama E. Rahma

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Immunology, Programmed Cell Death 1 Receptor, Antineoplastic Agents, Pembrolizumab, Biology, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Atezolizumab, Internal medicine, Neoplasms, medicine, Tumor Microenvironment, Immunology and Allergy, Animals, Humans, Molecular Targeted Therapy, Lung cancer, Melanoma, Tumor-infiltrating lymphocytes, Immunotherapy, medicine.disease, Immune checkpoint, 030104 developmental biology, 030220 oncology & carcinogenesis, Nivolumab, Signal Transduction
Abstract

Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers. This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 or PD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.

Published
2016

181. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial

Author

Jeffrey S. Weber, Theodore F. Logan, Elmer Berghorn, Jeffrey A. Sosman, Suresh G. Nair Md, Donald P. Lawrence, Leslie A. Fecher, Christine Horak, George Kong, Lynn M. Schuchter, Craig L. Slingluff, Geoff Gibney, Joel Jiang, F. Stephen Hodi, Elizabeth I. Buchbinder, Mary Ruisi, and Ryan J. Sullivan

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Skin Neoplasms, Population, Phases of clinical research, Ipilimumab, Drug Administration Schedule, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Clinical endpoint, Humans, Adverse effect, education, Survival rate, Melanoma, Aged, Neoplasm Staging, education.field_of_study, business.industry, Antibodies, Monoclonal, Middle Aged, Prognosis, Surgery, Survival Rate, 030104 developmental biology, Nivolumab, Oncology, 030220 oncology & carcinogenesis, Female, business, medicine.drug, Follow-Up Studies
Abstract

Summary Background Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6–62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1–55·3] of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4–53·8] vs 14 [20%; 11·4–31·3]). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8–25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7–not reached), whereas over a median follow-up of 14·7 months (IQR 5·6–23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2–26·5; HR 0·48 [95% CI 0·29–0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64–85 vs 54%; 42–65). Interpretation Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. Funding Bristol-Myers Squibb.

Published
2016

182. Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases

Author

Walter C. Olson, Craig L. Slingluff, Kelly T. Smith, David W. Mullins, Rachael A. Clark, Nadedja Galeassi, Mark E. Smolkin, Ileana S. Mauldin, Ena Wang, Francesco M. Marincola, Jessica E. Teague, Anne M. Stowman, Nolan A. Wages, Donna H. Deacon, Gina R. Petroni, and Kimberly A. Chianese-Bullock

Subjects
0301 basic medicine, Male, Cancer Research, Enzyme-Linked Immunospot Assay, Skin Neoplasms, medicine.medical_treatment, Administration, Topical, T-Lymphocytes, Imiquimod, 0302 clinical medicine, Cell Movement, Immunology and Allergy, Medicine, Cytotoxic T cell, Melanoma, Cells, Cultured, Middle Aged, Combined Modality Therapy, Oncology, 030220 oncology & carcinogenesis, Vaccines, Subunit, Aminoquinolines, Cytokines, Female, Infiltration (medical), medicine.drug, Immunology, Antineoplastic Agents, Cancer Vaccines, Article, 03 medical and health sciences, Immune system, Lymphocytes, Tumor-Infiltrating, Antigens, Neoplasm, Humans, Aged, Neoplasm Staging, business.industry, Immunotherapy, TLR7, medicine.disease, Peptide Fragments, 030104 developmental biology, Toll-Like Receptor 7, Cancer research, Cancer vaccine, business, Transcriptome
Abstract

Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases.Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression.Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.

Published
2016

183. From bench to bedside a comprehensive review of pancreatic cancer immunotherapy

Author

Paul R. Kunk, Osama E. Rahma, Todd W. Bauer, and Craig L. Slingluff

Subjects
Tumor Immunology, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Immunology, Review, 03 medical and health sciences, 0302 clinical medicine, Pancreatic tumor, Internal medicine, Pancreatic cancer, Cancer vaccine, medicine, Immunology and Allergy, Survival rate, Pharmacology, business.industry, Immunotherapy, medicine.disease, Immune checkpoint, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine, Personalized medicine, Pancreas, business
Abstract

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field.

Published
2016

184. Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate

Author

Jochen T. Schaefer, Kariman Chaba, Sylvain Ladoire, David Enot, Laurence Zitvogel, Gulsun Erdag, Vichnou Poirier-Colame, Donna H. Deacon, François Ghiringhelli, Guido Kroemer, Craig L. Slingluff, Laura Senovilla, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Surgery, Division of Surgical Oncology-University of Virginia School of Medicine, Department of pathology [Virginia], University of Virginia [Charlottesville], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska Institutet [Stockholm], Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), University of Virginia, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Hmgb1 Expression, CD3, Immunology, T-Cells, chemical and pharmacologic phenomena, Immunogenic Cell Death, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Immune system, medicine, Autophagy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, Cell-Death, Breast-Cancer, Melanoma, Lc3b Puncta, Original Research, Hmgb1, biology, Anticancer Chemotherapy, Immune Infiltrates, Immunosurveillance, FOXP3, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, Cancer research, biology.protein, Lc3, Immunogenic cell death, [SDV.IMM]Life Sciences [q-bio]/Immunology, Mechanism, Therapy, Calreticulin, CD8
Abstract

International audience; Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2 alpha; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3. LC3B puncta positively correlated with the infiltration of metastases by CD163(+) macrophages, while expression of HMGB1 correlated with infiltration by FOXP3(+) regulatory T cells and CD56(+) lymphocytes. eIF2 alpha phosphorylation was associated with an augmentation of nuclear diameters, reflecting an increase in ploidy. Interestingly, therapeutic vaccination led to a reduction of eIF2 alpha phosphorylation suggestive of immunoselection against cells bearing this sign of endoplasmic reticulum (ER) stress. None of the stress/death-related biomarkers had a significant prognostic impact, contrasting with the major prognostic effect of the ratio of cytotoxic T lymphocytes (CTL) over immunosuppressive FOXP3(+) and CD163(+) cells. Altogether, these results support the idea of a mutual dialog between, on one hand, melanoma cells with their cell-intrinsic stress pathways and, on the other hand, immune effectors. Future work is required to understand the detailed mechanisms of this interaction.Keywords

Published
2016

185. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015

Author

Erik Wennerberg, Gabriele Madonna, Gennaro Ciliberto, Michele Minopoli, Caroline Dutriaux, Matthew Wongchenko, Elisabetta Gambale, David F. Stroncek, Céleste Lebbé, Ani S. Balmanoukian, Gianluca Di Monta, Vincenzo Ingangi, Soldano Ferrone, Ivan Marquez-Rodas, Giuseppe Masucci, Janis M. Taube, Simona Mastroeni, Gerardo Bott, Franck Pagès, Jonathan M. Pitt, Judit Olasz, Elisabetta Panza, Paola Michelozzi, Daniil Stoyakovskiy, Stéphane Dalle, Mario Sznol, John M. Kirkwood, Keith T. Flaherty, Maria Capuano, Amalia Azzariti, Edward Cha, Peter Boasberg, Maria Godeny, Angela Gismondi, Ornella Franzese, Giusy Gentilcore, Jean-Jacques Grob, Olivier Michielin, Adina Elena Stanciu, Giuseppe Cirino, Julien Fourcade, Nelofer Syed, Giuseppe Ercolano, Caroline Robert, Ascierto Paolo Antonio, Christine K. Gause, Silviu Voinea, Adeeb Rahman, Anne Caignard, Camila Flores, Cristina Fortes, Yuya Yoshimoto, Angela Sandru, Andras Szollar, Monica Cantile, Frederic Lehmann, Maria Libera Ascierto, Sacha Gnjatic, Marco Tucci, Rosa Russo, Giuseppina Liguori, Valeria De Biasio, David Ross Kaufman, Mary Ruisi, Ewa Kalinka-Warzocha, Phillip Wong, Rosaria Falcon, Vincenzo Faiola, Nicole Richie, Lars Ny, Miri Blank, Paola De Cicco, Anna Passarelli, Jean-François Baurain, Guido Kroemer, Claudio Jommi, Francesca Capone, Maria Teresa Fierro, Tracee L. McMiller, Lev V. Demidov, Alessandro Testori, Omid Hamid, Marone Ugo, Annamaria Anniciello, Andrew J. Park, Fara De Murtas, RuthAnn Gordan, Emil Farkas, David Hogg, Alessandra Di Paolo, Mark Maurer, Yangyang Wang, Mario Mandalà, Rodabe N. Amaria, Massimiliano Di Marzo, Stefania Guida, Luigi Fattore, Veronica Huber, Ludmila Danilova, Luigi Aurisicchio, Gabriella Aquino, Domenico Mallardo, Catriona M. McNeil, Stephanie Anne Kronenberg, Consiglia Carella, Theresa S. Pritchard, Katia Bifulco, Michaela Semeraro, Carlo M. Croce, David P. Enot, Laurence Zitvogel, Marcella Occelli, Benjamin Weide, Magdalena Thurin, Margherita Cerrone, Naiyer A. Rizvi, Blessing Agunwamba, Stella D'Oronzo, Sarah Jegou, Stucci Stefania, Drew M. Pardoll, Vito Michele Garrisi, Haidong Tang, Szabolcs Horvath, Hong Wang, Benjamin Brady, Antonio Doronzo, Claudia Marino, Xian He, Michael A. Davies, Hexiao Wang, Isabelle Rooney, Orsolya Csuka, Maurizio Nudo, Lance Leopold, Jeffrey S. Wasser, Sabino Strippoli, Silvia Ch Formenti, MariaLaura Foddai, Michael A. Postow, Robert H.I. Andtbacka, Paul Lorigan, Tommy Andersson, Naoko Imai, Ari VanderWalde, Mariaelena Capone, Ilsung Chang, Laura Lattanzio, Carmen Loquai, Arantxa Sancho, Christine Horak, Federica Sallusto, Timea Balatoni, Maha Ayyoub, Angela Santoni, Alessio Caggiati, Anna Lisa De Presbiteris, Henrik Schmidt, Paola Savoia, Pontus Berglund, Igor Puzanov, Aurélien Marabelle, Ana Carrizossa Anderson, Hassane M. Zarour, Maria Wolodarski, Patrick Hwu, Joel Jiang, Pio Zeppa, Jeffrey A. Sosman, Eugenio Fernandez, Susan Costantini, Marcus Ballinger, Luc Thomas, Leslie Cope, Rolf Kiessling, Christophe Borg, Francesca Platini, Florian Stratica, Tilman T. Rau, Craig L. Slingluff, Paolo A. Ascierto, Angela Ianaro, Harriet M. Kluger, Stephen Hodi, Tara C. Gangadhar, Claire Vanpouille-Box, Caroline Flament, Hearn J. Cho, Mannavola Francesco, Takahiro Yamazaki, Charles G. Drake, Jason J. Luke, Miklos Kasler, Linda Pan, Caracò Corrado, Alfonso Berrocal, Angel Rivera, Vera Hirsh, Eduardo J. Patriarca, Giovanni Di Giulio, Antonello Pessi, Helena Stabile, Helene Hardy, Tucci Marco, Ralph Venhaus, Maria Luisa Di Cecilia, Catherine A. Harwood, Jonathan Cebon, Anna Maria Anniciello, Grant A. McArthur, Carlo Baldi, Ahmad A. Tarhini, Shelley Coleman, Gil Bar-Sela, Axel Hauschild, Byoung S. Kwon, Maria Paula Roberti, Sabin Cinca, Tiziana Cocco, Valeria Sorrentino, Jeffrey Wallin, Rosa Camerlingo, Sandra Demaria, Jedd D. Wolchok, Isabel Poschke, Alessandro Lugli, Michael B. Atkins, Andrea Cavalcanti, Laura Marra, Rosamaria Pinto, Adam D. Cohen, Michele Maio, Weiyi Peng, Rosario Guarrasi, David Enot, Antoni Ribas, Oscar Alabiso, Chiara Armogida, Silvestris Franco, Jessica C. Hassel, Rita Mancini, Michele Guida, Silvia C. Formenti, Andrea P. Sponghini, Imma Maida, Alba Zappalà, Charlotte M. Proby, Alan J. Korman, Yibing Yan, Matias Chacon, Haiying Xu, Carolin Blattner, Maria-Paula Roberti, Lisa Chen, James Larkin, Ryan J. Sullivan, Madonna Gabriele, Nadege Vimond, Cosmo Di Donna, Farnaz Moradi, Manish R. Patel, Sylvie Rusakiewicz, Francesca Passarelli, Luis de la Cruz-Merino, Nicolas Jacquelot, Roberta Miceli, Viktor Umansky, Akos Savolt, David Rondonotti, Gabriella Liszkay, Jianda Yuan, Stefani Spranger, Yufan Zhao, Yehuda Shoenfeld, Todd M. Bauer, Claus Garbe, Joe-Marc Chauvin, Achim A. Jungbluth, Cristiana Lo Nigro, Alexander M. Lesokhin, Gabriella Guida, Brigitte Dréno, Cindy Sanders, Jeffrey S. Weber, Janet Maleski, Chris Cheadle, Romain Daillère, Isabella Sperduti, Michaele Maio, Claudia Felici, Parneet K. Cheema, Concetta Ragone, Johan Hansson, Klara Eles, Victoria Atkinson, Speiser Daniel, Daniel O. Koralek, Zhaojun Sun, Debora Malpicci, Elena Marra, Rickard Linnskog, Jeffrey Chou, Yang Wang, Eugenia Panaitescu, F. Stephen Hodi, Anthony J. Olszanski, Chiara Botti, Nicola Mozzillo, Anna Ferretta, Paul B. Chapman, Michaë la Semeraro, Belinda Palermo, Francesco Sabbatino, Neil H. Segal, Yago Pico de Coaña, Tseng-hui Timothy Chen, Ornella Pagliano, John B. A. G. Haanen, Huibin Yue, Emilia Caputo, Alan E. Berger, Simona De Summa, Nikoletta Lendvai, Paola Queirolo, Francesco Mannavola, Thomas F. Gajewski, Michele De Tursi, Paola Nisticò, Karen Briscoe, Karmele Mujika Eizmendi, Maria Vincenza Carrier, Passarelli Anna, Laurent Mortier, Crescenzo D'Alterio, Jorge Camarero, Licia Rivoltini, Pietro Quaglino, Davide Quaresmini, Marie Vétizou, Anna Maria Di Giacomo, Chandra Prakash Prasad, Riccardo Bono, Vichnou Poirier-Colame, David Smith, Capone Mariaelena, Giosuè Scognamiglio, Margaret K. Callahan, Vashisht Gopal Yennu Nanda, Fabiola Gilda Cordaro, George J. Netto, Madalina Bolovan, Federica Fratangelo, Josep Malvehy, Robert A. Anders, Karsten A. Pilones, Vincenzo C. Battarra, Karin Leandersson, Maria Letizia Motti, Yang Xin Fu, Tim Crook, Sarah Nataraj, Alastair M. Thompson, Franco Silvestris, Carolina Cauchi, Georgina V. Long, Holbrook E Kohrt, Giuseppe Pirozzi, Celeste Fusciello, Marco Carlo Merlano, François Aubin, Mozzillo Nicola, Giuseppe Cirin, Stefania Scala, Suzanne L. Topalian, Alexander M.M. Eggermont, Antonio Marra, Jinshui Fan, Reinhard Dummer, Federica Zito Marino, Amanda Ralabate, Matthew M. Burke, Piotr Rutkowski, Gerardo Botti, Stefano Pepe, Ivor Caro, and Stefania Tommasi

Subjects
0301 basic medicine, business.industry, MEDLINE, General Medicine, medicine.disease, Bridge (interpersonal), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Medical emergency, business
Published
2016

186. Amelanotic melanomas presenting as red skin lesions: a diagnostic challenge with potentially lethal consequences

Author

Kira B. Mayo, Mark E. Smolkin, Craig L. Slingluff, Susannah E. McClain, Amber L. Shada, and James W. Patterson

Subjects
medicine.medical_specialty, Pathology, medicine.diagnostic_test, business.industry, Melanoma, Retrospective cohort study, Dermatology, Physician education, medicine.disease, Metastasis, Medicine, In patient, Differential diagnosis, business, Skin lesion, neoplasms, Shave biopsy
Abstract

Objective To characterize epidemiologic and clinical features of red primary amelanotic melanomas, an atypical presentation of melanoma that is underemphasized in patient and physician education. Patients and methods Review of a prospectively collected melanoma database identified 46 patients with red amelanotic melanomas, whose clinical features were compared with 329 patients with pigmented melanomas from the same database and same timeframe from January 1964 to September 2005. Results Red amelanotic melanomas represented 3.9% of all melanomas recorded in our database and accounted for nearly 70% of amelanotic melanomas. Melanoma was included in the clinical differential diagnosis in 32% of red amelanotic melanomas vs. 94% of pigmented melanomas (P

Published
2012

187. Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma

Author

Lynn T. Dengel, Donna H. Deacon, Gulsun Erdag, Craig L. Slingluff, Sofia M. Shea, Jochen T. Schaefer, James W. Patterson, and Mark E. Smolkin

Subjects
Adult, Male, Cancer Research, Skin Neoplasms, T-Lymphocytes, Article, Immunophenotyping, Young Adult, Lymphocytes, Tumor-Infiltrating, Immune system, Tumor Microenvironment, medicine, Humans, Survivors, Melanoma, B cell, Aged, Aged, 80 and over, B-Lymphocytes, Tumor microenvironment, business.industry, Macrophages, Dendritic Cells, Middle Aged, biochemical phenomena, metabolism, and nutrition, medicine.disease, Lymphocyte Subsets, medicine.anatomical_structure, Oncology, Tumor progression, Immunology, Female, business, Infiltration (medical), CD8
Abstract

Immune cells infiltrating the microenvironment of melanoma metastases may either limit or promote tumor progression, but the characteristics that distinguish these effects are obscure. In this study, we systematically evaluated the composition and organization of immune cells that infiltrated melanoma metastases in human patients. Three histologic patterns of immune cell infiltration were identified, designated immunotypes A, B, and C. Immunotype A was characterized by no immune cell infiltrate. Immunotype B was characterized by infiltration of immune cells limited only to regions proximal to intratumoral blood vessels. Immunotype C was characterized by a diffuse immune cell infiltrate throughout a metastatic tumor. These immunotypes represented 29%, 63%, and 8% of metastases with estimated median survival periods of 15, 23, and 130 months, respectively. Notably, from immunotypes A to C, there were increasing proportions of B cells and decreasing proportions of macrophages. Overall, the predominant immune cells were T cells (53%), B cell lineage cells (33%), and macrophages (13%), with natural killer and mature dendritic cells only rarely present. Whereas higher densities of CD8+ T cells correlated best with survival, a higher density of CD45+ leukocytes, T cells, and B cells also correlated with increased survival. Together, our findings reveal striking differences in the immune infiltrate in melanoma metastases in patients, suggesting microenvironmental differences in immune homing receptors and ligands that affect immune cell recruitment. These findings are important, not only by revealing how the immune microenvironment can affect outcomes but also because they reveal characteristics that may help improve individualized therapy for patients with metastatic melanoma. Cancer Res; 72(5); 1070–80. ©2012 AACR.

Published
2012

188. The Vaccine-site Microenvironment Induced by Injection of Incomplete Freund's Adjuvant, With or Without Melanoma Peptides

Author

Louis B. Brill, James W. Patterson, Donna H. Deacon, Gina R. Petroni, Kimberly A. Chianese-Bullock, Jochen T. Schaefer, Rebecca C. Harris, Craig L. Slingluff, and Kerrington R. Molhoek

Subjects
Cancer Research, Skin Neoplasms, Injections, Intradermal, medicine.medical_treatment, T cell, Freund's Adjuvant, Immunology, High endothelial venules, Immunization, Secondary, Neovascularization, Physiologic, Cell Communication, Cancer Vaccines, T-Lymphocytes, Regulatory, Article, Immunomodulation, Antigens, Neoplasm, Cell Movement, T-Lymphocyte Subsets, Humans, Immunology and Allergy, Medicine, Antigen-presenting cell, Melanoma, Skin, Pharmacology, B-Lymphocytes, business.industry, Granulocyte-Macrophage Colony-Stimulating Factor, Forkhead Transcription Factors, Dendritic Cells, Immunotherapy, Lipids, Peptide Fragments, Vaccination, medicine.anatomical_structure, Cellular Microenvironment, Freund's adjuvant, Cytokines, Cancer vaccine, business, Adjuvant
Abstract

Cancer vaccines have not been optimized. They depend on adjuvants to create an immunogenic microenvironment for antigen presentation. However, remarkably little is understood about cellular and molecular changes induced by these adjuvants in the vaccine microenvironment. We hypothesized that vaccination induces dendritic cell activation in the dermal vaccination microenvironment but that regulatory processes may also limit the effectiveness of repeated vaccination. We evaluated biopsies from immunization sites in two clinical trials of melanoma patients. In one study (Mel38), patients received one injection with an adjuvant mixture alone, comprised of incomplete Freund's adjuvant (IFA) plus granulocyte-macrophage colony stimulating factor (GM-CSF). In a second study, patients received multiple vaccinations with melanoma peptide antigens plus IFA. Single injections with adjuvant alone induced dermal inflammatory infiltrates consisting of B cells, T cells, mature dendritic cells (DC) and vessels resembling high endothelial venules (HEV). These cellular aggregates usually lacked organization and were transient. In contrast, multiple repeated vaccinations with peptides in adjuvant induced more organized and persistent lymphoid aggregates containing separate B and T cell areas, mature DC, HEV-like vessels, and lymphoid chemokines. Within these structures, there are proliferating CD4+ and CD8+ T lymphocytes, as well as FoxP3+CD4+ lymphocytes, suggesting a complex interplay of lymphoid expansion and regulation within the dermal immunization microenvironment. Further study of the physiology of the vaccine site microenvironment promises to identify opportunities for enhancing cancer vaccine efficacy by modulating immune activation and regulation at the site of vaccination.

Published
2012

189. Achieving Sufficient Accrual to Address the Primary Endpoint in Phase III Clinical Trials from U.S. Cooperative Oncology Groups

Author

Monika J. Thielen, Craig L. Slingluff, Robert Gray, Daniel J. Sargent, D L Wickerham, Hongkun Wang, Gina R. Petroni, Jacqueline Benedetti, Benjamin Djulbegovic, Anneke T. Schroen, Walter M. Cronin, and Xiaofei Wang

Subjects
Research design, Oncology, Cancer Research, medicine.medical_specialty, Phase iii trials, Accrual, MEDLINE, Phases of clinical research, Article, Neoplasms, health services administration, Internal medicine, medicine, Clinical endpoint, Humans, health care economics and organizations, business.industry, digestive, oral, and skin physiology, food and beverages, Interim analysis, humanities, Clinical trial, Clinical Trials, Phase III as Topic, Research Design, business
Abstract

Purpose: Assessing impact of poor accrual on premature trial closure requires a relevant metric. We propose defining accrual sufficiency on apparent ability to address primary endpoints (PE) rather than attaining accrual targets. Experimental Design: All phase III trials open January 1, 1993, to December 31, 2002, by five U.S. oncology Clinical Trials Cooperative Groups (CTCG) were evaluated for accrual sufficiency and scientific results. Sufficient accrual included meeting accrual target, CTCGs documentation attesting adequate accrual, or conclusive results at interim analysis; insufficient accrual included poor accrual as cited closure reason or other reasons rendering a trial unable to address its primary endpoints. Closure rates based on our accrual sufficiency definition are compared with rates of meeting accrual targets and addressing the primary endpoints. A percentage of target accrual above which trials commonly answer the intended scientific question was identified to serve as an alternative to meeting full target accrual in designating accrual success. Results: Of 238 eligible trials, 158 (66%) closed with sufficient accrual. Among 80 trials with insufficient accrual, 70 (29%) closed specifically because of poor accrual. Inadequate accrual rates are overemphasized when defining accrual success solely by meeting accrual targets. Nearly 75% of trials conclusively addressed the primary endpoints with positive results in 39% of trials. Exceeding 80% of target accrual serves as a reliable proxy for answering the intended scientific question. Conclusions: Approximately one third of phase III trials closed with insufficient accrual to address the primary endpoints, primarily due to poor accrual. Defining accrual sufficiency broader than meeting accrual targets represents a fairer account of trial closures. Clin Cancer Res; 18(1); 256–62. ©2011 AACR.

Published
2012

190. A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites

Author

Nikole Varhegyi, Kimberly A. Chianese-Bullock, Caroline M. Reed, Walter C. Olson, Ileana S. Mauldin, William W. Grosh, Sean B. Donnelly, Donna H. Deacon, Gina R. Petroni, Nadejda V. Galeassi, Kelly T. Smith, Craig L. Slingluff, Kristy Scott, and Mark E. Smolkin

Subjects
Adult, Cancer Research, medicine.drug_class, T cell, Immunology, Pilot Projects, Peripheral blood mononuclear cell, Immunostimulant, Cancer Vaccines, Injections, Intramuscular, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Adjuvants, Immunologic, Antigens, Neoplasm, medicine, Immunology and Allergy, Humans, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, ELISPOT, Melanoma, Middle Aged, medicine.disease, Neoplasm Proteins, medicine.anatomical_structure, Treatment Outcome, Oncology, Immunization, 030220 oncology & carcinogenesis, business, CD8, 030215 immunology
Abstract

Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m. but not i.d. or s.c. This study tests hypotheses that the i.d./s.c. route is safe and will increase CD4(+) and CD8(+) T cell responses to MAGE-A3.Twenty-five patients with resected stage IIB-IV MAGE-A3(+) melanoma were randomized to immunization with recMAGE-A3 combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) either i.m. (group A, n = 13) or i.d./s.c. (group B, n = 12). Adverse events were recorded. Ab responses to MAGE-A3 were measured by ELISA. T cell responses to overlapping MAGE-A3 peptides were assessed in PBMC and a sentinel immunized node (SIN) after 1 in vitro stimulation with recMAGE-A3, by IFN-γ ELISPOT assay and by flow cytometry for multifunctional (TNF-α/IFN-γ) responses.Both routes of immunization were well tolerated without treatment-related grade 3 adverse events. All patients had durable Ab responses. For all 25 patients, the T cell response rate by ELISPOT assay was 30 % in SIN (7/23) but only 4 % (1/25) in PBMC. By flow cytometry, multifunctional CD8(+) T cell responses were identified in one patient in each group; multifunctional CD4(+) T cell response rates for groups A and B, respectively, were 31 and 64 % in SIN and 31 and 50 % in PBMC.The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4(+) T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration.

Published
2015

191. Molecular Insights on the Peripheral and Intratumoral Effects of Systemic High-Dose rIL-2 (Aldesleukin) Administration for the Treatment of Metastatic Melanoma

Author

Yingdong Zhao, William W. Grosh, Geoffrey R. Weiss, Ena Wang, Craig L. Slingluff, Hui Liu, Kimberly A. Chianese-Bullock, and Francesco M. Marincola

Subjects
Adult, Male, Interleukin 2, Cancer Research, Antineoplastic Agents, Biology, Peripheral blood mononuclear cell, Article, Immune system, Aldesleukin, Interferon, Tumor Microenvironment, medicine, Humans, Neoplasm Metastasis, Melanoma, Aged, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, Tumor microenvironment, Interleukin-17, Middle Aged, medicine.disease, Recombinant Proteins, Gene Expression Regulation, Neoplastic, Oncology, Immunology, Leukocytes, Mononuclear, Interleukin-2, Female, medicine.drug
Abstract

Purpose: We have previously shown that within tumors, recombinant interleukin-2 (rIL-2, aldesleukin) consistently activates tumor-associated macrophages and upregulates IFN-stimulated genes while inducing minimal migration, activation, or proliferation of T cells. These effects are independent of tumor response to treatment. Here, we prospectively evaluated transcriptional alterations induced by rIL-2 in peripheral blood mononuclear cells (PBMC) and within melanoma metastases. Experimental Design: We evaluated gene expression changes by serially comparing pre- to posttreatment samples in 13 patients and also compared transcriptional differences among lesions displaying different responsiveness to therapy, focusing on 2 lesions decreasing in size and 2 remaining stable (responding lesions) compared with nonresponding ones. Results: As previously described, the effects of rIL-2 were dramatic within PBMCs, whereas effects within the tumor microenvironment were lesion specific and limited. However, distinct signatures specific to response could be observed in responding lesions pretreatment that were amplified following rIL-2 administration. These signatures match the functional profile observed in other human or experimental models in which immune-mediated tissue-specific destruction (TSD) occurs, underscoring common pathways leading to rejection. Moreover, the signatures observed in pretreatment lesions were qualitatively similar to those associated with TSD, underlining a determinism to immune responsiveness that depends upon the genetic background of the host or the intrinsic genetic makeup of individual tumors. Conclusions: This is the first prospectively collected insight on global transcriptional events occurring during high-dose rIL-2 therapy in melanoma metastases responding to treatment. Clin Cancer Res; 17(23); 7440–50. ©2011 AACR.

Published
2011

192. Challenges to accrual predictions to phase III cancer clinical trials: a survey of study chairs and lead statisticians of 248 NCI-sponsored trials

Author

Anneke T. Schroen, D L Wickerham, Benjamin Djulbegovic, Daniel J. Sargent, Xiaofei Wang, Robert Gray, Hongkun Wang, Gina R. Petroni, Jacqueline Benedetti, Monika J. Thielen, Craig L. Slingluff, Wendy F. Cohn, and Walter M. Cronin

Subjects
Research design, medicine.medical_specialty, Accrual, Biostatistics, Medical Oncology, Article, Surveys and Questionnaires, health services administration, medicine, Humans, Patient participation, health care economics and organizations, Pharmacology, Response rate (survey), Internet, business.industry, Data Collection, Patient Selection, digestive, oral, and skin physiology, food and beverages, General Medicine, Interim analysis, National Cancer Institute (U.S.), United States, humanities, Clinical trial, Clinical Trials, Phase III as Topic, Research Design, Therapeutic Equipoise, Physical therapy, Patient Participation, business, Statistician
Abstract

Background Research on barriers to accrual has typically emphasized factors influencing participation after trial activation. Purpose We sought to identify factors influencing trial design and accrual predictions prior to trial activation associated with sufficient accrual. Methods A 30-question web-based survey was sent to the study chair and lead statistician for all 248 phase III trials open in 1993–2002 by five Clinical Trials Cooperative Groups. Questions addressed prior trial experience, trial design elements, accrual predictions, and perceived accrual influences. Accrual sufficiency categorization was derived from Clinical Trials Cooperative Group records: sufficient accrual included trials closed with complete accrual or at interim analysis, insufficient accrual included trials closed with inadequate accrual. Responses were analyzed by respondent role (study chair/lead statistician) and accrual sufficiency. Results Three hundred and nine eligible responses were included (response rate, 63%; lead statisticians, 81%; and study chairs, 45%), representing trials with sufficient (63%) and insufficient accruals (37%). Study chair seniority or lead statistician experience was not linked to accrual sufficiency. Literature review, study chair's personal experience, and expert opinion within Clinical Trials Cooperative Group most commonly influenced control arm selection. Clinical Trials Cooperative Group experience most influenced accrual predictions. These influences were not associated with accrual sufficiency. Among respondents citing accrual difficulties (41%), factors negatively influencing accrual were not consistently identified. Respondents credited three factors with positively influencing accrual: clinical relevance of study, lack of competing trials, and protocol paralleling normal practice. Limitations Perceptions of lead statisticians and study chairs may not accurately reflect accrual barriers encountered by participating physicians or patients. Survey responses may be subject to recall bias. Conclusion Consistent factors explaining poor accrual were not identified, suggesting reasons for poor accrual are not well understood and warrant further study. Alternate strategies for accrual prediction are needed since Clinical Trials Cooperative Group experience is linked to successful and unsuccessful accrual.

Published
2011

193. Surgical resection for bulky or recurrent axillary metastatic melanoma

Author

Dustin M. Walters, Shannon N. Tierney, Amber L. Shada, and Craig L. Slingluff

Subjects
Surgical resection, medicine.medical_specialty, Metastatic melanoma, business.industry, medicine.medical_treatment, Melanoma, Retrospective cohort study, General Medicine, medicine.disease, Surgery, Axilla, medicine.anatomical_structure, Oncology, medicine, Lymphadenectomy, business, Prospective cohort study, Survival rate
Abstract

Introduction Metastatic melanoma has few FDA approved treatments, and aggressive surgical resection has to be considered for management of bulky axillary metastases. We hypothesized that axillary resection in this setting is well tolerated and improves symptoms in the majority of patients.

Published
2011

194. Comprehensive analysis of receptor tyrosine kinase activation in human melanomas reveals autocrine signaling through IGF-1R

Author

David L. Brautigan, Jason A. Papin, Mark E. Smolkin, Sudhir Chowbina, Craig L. Slingluff, Amber L. Shada, and Kerrington R. Molhoek

Subjects
Cancer Research, biology, Cell growth, Melanoma, Dermatology, medicine.disease, Receptor tyrosine kinase, Cell biology, Oncology, Fibroblast growth factor receptor, Cell culture, biology.protein, medicine, Receptor, Autocrine signalling, neoplasms, Insulin-like growth factor 1 receptor
Abstract

Melanomas depend on autocrine signals for proliferation and survival; however, no systematic screen of known RTKs has been performed to identify which autocrine signaling pathways are activated in melanoma. Here we performed a comprehensive analysis of 42 receptor tyrosine kinases (RTKs) in 6 individual human melanoma tumor specimens as well as 17 melanoma cell lines, some of which were derived from the tumor specimens. We identified 5 RTKs that were active in almost every one of the melanoma tissue specimens and cell lines, including two previously unreported receptors, IGF1R and MSPR, in addition to three receptors (VEGFR, FGFR and HGFR) known to be autocrine activated in melanoma. We show by real time quantitative PCR that all melanoma cell lines expressed genes for the RTK ligands HGF, IGF1 and MSP. Addition of antibodies to either IGF1 or HGF, but not to MSP, to the culture medium blocked melanoma cell proliferation, and even caused net loss of melanoma cells. Antibody addition deactivated IGF1R and HGFR receptors, as well as MAPK signaling. Thus, IGF1 is a new growth factor for autocrine driven proliferation of human melanoma in vitro. Our results suggest that IGF1-IGF1R autocrine pathway in melanoma is a possible target for therapy in human melanomas.

Published
2011

195. VEGFR-2 expression in human melanoma: Revised assessment

Author

James W. Patterson, Cheryl F. Murphy, Craig L. Slingluff, Kerrington R. Molhoek, J K Rasamny, Gulsun Erdag, David L. Brautigan, and Donna H. Deacon

Subjects
Cancer Research, Immunoblotting, Biology, Antibodies, Article, chemistry.chemical_compound, Cell Line, Tumor, medicine, Humans, Neoplasm Metastasis, Autocrine signalling, Melanoma, integumentary system, Transfection, medicine.disease, Immunohistochemistry, Vascular Endothelial Growth Factor Receptor-2, Molecular biology, Vascular endothelial growth factor, Oncology, chemistry, Tissue Array Analysis, Cell culture, embryonic structures, cardiovascular system, biology.protein, Antibody, Immunostaining
Abstract

Vascular endothelial growth factor (VEGF) is an angiogenic factor that also functions as an autocrine growth factor for VEGF receptor (VEGFR)-2(+) melanomas. In multiple studies, VEGFR-2 was detected by immunostaining in 78-89% of human melanoma cells, suggesting that most patients with melanoma would benefit from anti-VEGF therapy. Here, we evaluated 167 human melanoma specimens in a tissue microarray to verify the presence of VEGFR-2, but found disparities in staining with commercial antibodies A-3 and 55B11. Antibody A-3 stained melanoma cells in 79% of specimens, consistent with published results; however, we noted extensive nonspecific staining of other cells such as smooth muscle and histiocytes. In contrast, antibody 55B11 stained melanoma cells in only 7% (95% confidence interval: 3.3-11.5) of specimens. As an internal positive control for VEGFR-2 detection, vascular endothelial cells were stained with antibody 55B11 in all specimens. We compared VEGFR-2(+) and VEGFR-2(-) melanoma cell lines by immunoblotting and immunohistochemistry after small interfering RNA (siRNA) knockdown and transient overexpression of VEGFR-2 to validate antibody specificity. Immunoblotting revealed that A-3 primarily cross-reacted with several proteins in both cell lines and these were unaffected by siRNA knockdown of VEGFR-2. In contrast, 55B11 staining of VEGFR-2(+) cells was mostly eliminated by siRNA knockdown of VEGFR-2 and increased in VEGFR-2(-) melanoma cell lines following transfection to express ectopic VEGFR-2. Our results show that relatively few melanoma cells (10%) express detectable levels of VEGFR-2, and therefore, the majority of patients with melanoma are unlikely to benefit from antiproliferative effects of anti-VEGF therapy.

Published
2011

196. Evaluation of molecular markers of mesenchymal phenotype in melanoma

Author

Craig L. Slingluff, Gulsun Erdag, Leann M. Mikesh, Marty W. Mayo, Kerrington R. Molhoek, Kevin T. Hogan, and Manish Kumar

Subjects
Male, Cancer Research, Pathology, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Lung Neoplasms, Vimentin, Dermatology, Biology, Article, Metastasis, Transforming Growth Factor beta1, Antigens, CD, Transforming Growth Factor beta, Cell Line, Tumor, Biomarkers, Tumor, medicine, Humans, Epithelial–mesenchymal transition, Melanoma, Tumor Necrosis Factor-alpha, Cadherin, digestive, oral, and skin physiology, Mesenchymal stem cell, Transforming growth factor beta, Cadherins, medicine.disease, Immunohistochemistry, Phenotype, Oncology, Cancer research, biology.protein, Female, Snail Family Transcription Factors, Transcription Factors
Abstract

The epithelial to mesenchymal transition is a developmental process allowing epithelial cells to dedifferentiate into cells displaying mesenchymal phenotypes. The pathological role of epithelial to mesenchymal transition has been implicated in invasion and metastasis for numerous carcinomas, yet limited data exist addressing whether mesenchymal transition (MT) occurs in malignant melanoma cells. Our group developed an in-vitro three-dimensional culture system to address MT in melanoma cells upon transforming growth factor-β/ tumor necrosis factor-α treatment. Loss of E-cadherin is one of the best indicators of MT in epithelial cells. Not surprisingly, E-cadherin was expressed in only three of 12 (25%) melanoma cell lines and all three mesenchymal proteins, N-cadherin, vimentin, and fibronectin, were expressed by seven (58%) melanoma cell lines. However, after cytokine treatment, two or more mesenchymal proteins were elevated in nine (75%) melanoma cell lines. Data support the transforming growth factor-β production by melanoma cells which may induce/support MT. Evaluation of E-cadherin, N-cadherin, and Snail expression in melanoma tissue samples are consistent with an inverse coupling of E-cadherin and N-cadherin expression, however, there are also examples suggesting a more complex control of their expression. These results indicate that malignant melanoma cell lines are susceptible to MT after cytokine treatment and highlight the importance of understanding the effects of cytokines on melanoma to undergo MT.

Published
2010

198. Interface of Signal Transduction Inhibition and Immunotherapy in Melanoma

Author

Kerrington R. Molhoek, Amber L. Shada, and Craig L. Slingluff

Subjects
Drug, Cancer Research, medicine.medical_treatment, media_common.quotation_subject, Alpha interferon, Cancer Vaccines, Article, Targeted therapy, Immune system, Signal Transduction Inhibition, medicine, Animals, Humans, Molecular Targeted Therapy, Melanoma, media_common, business.industry, Immunotherapy, medicine.disease, Combined Modality Therapy, Oncology, Immunology, Cancer research, Signal transduction, business, Signal Transduction
Abstract

Food and Drug Administration-approved treatment for metastatic melanoma, including interferon alpha and interleukin-2, offer a modest benefit. Immunotherapy, although has not enjoyed high overall response rates, is capable of providing durable responses in a subset of patients. In recent years, new molecular-targeted therapies have become available and offer promise of clinical benefit, although low durability of response. It is not yet clear how best to integrate these 2 novel modalities that target the immune response to melanoma (immune therapy) or that target molecular signaling pathways in the melanoma cells (targeted therapy). Many signal transduction pathways are important in both tumor cell and T-cell proliferation and survival, which generate risk in combining targeted therapy and immunotherapy. This review focuses on the role of targeted therapy and immunotherapy in melanoma, and discusses how to combine the 2 modalities rationally for increased duration and response.

Published
2010

199. Phase 1 study of NY-ESO-1 vaccine + ipilimumab (IPI) in patients with unresectable or metastatic melanoma

Author

Philip Friedlander, Jedd D. Wolchok, Ralph Venhaus, Hassane M. Zarour, Aileen Ryan, Mary J. Macri, Kelly M Smith, Craig L. Slingluff, Craig Devoe, Donna H. Deacon, and Michael A. Postow

Subjects
Cancer Research, Metastatic melanoma, business.industry, medicine.medical_treatment, Ipilimumab, Immunotherapy, Oncology, Antigen, Immunity, hemic and lymphatic diseases, Cancer research, Medicine, In patient, NY-ESO-1, business, neoplasms, Advanced melanoma, medicine.drug
Abstract

e15175Background: IPI is an approved immunotherapy for advanced melanoma; it has enhanced spontaneous immunity to NY-ESO-1, a cancer-testis antigen expressed by some melanomas. NY-ESO-1 vaccines ha...

Published
2018

200. Pilot trial of an Indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor plus a multipeptide melanoma vaccine in patients with advanced melanoma

Author

Ileana S. Mauldin, Brian R. Gastman, Marc S. Ernstoff, Brent A. Hanks, Steven P. Fling, David H. Lawson, Keith A. Delman, Craig L. Slingluff, Judith C Kaiser, and Martin A. Cheever

Subjects
0301 basic medicine, Cancer Research, business.industry, medicine.medical_treatment, Melanoma, Pilot trial, Immunosuppression, medicine.disease, Melanoma Vaccine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, In patient, Indoleamine 2,3-dioxygenase, business, Infiltration (medical), Advanced melanoma
Abstract

3033Background: Melanoma metastases limit infiltration and function of antitumor T cells in part by immunosuppression with IDO1. INCB024360 (epacadostat) is an IDO1 inhibitor that normalizes serum ...

Published
2018

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