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1. A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes

Author

Marie-Andrée Forget, René J. Tavera, Cara Haymaker, Renjith Ramachandran, Shuti Malu, Minying Zhang, Seth Wardell, Orenthial J. Fulbright, Chistopher Leroy Toth, Audrey M. Gonzalez, Shawne T. Thorsen, Esteban Flores, Arely Wahl, Weiyi Peng, Rodabe N. Amaria, Patrick Hwu, and Chantale Bernatchez

Subjects
tumor-infiltrating lymphocytes, retroviral-transduction, adoptive cell therapy, genetic modification, Good Manufacturing Practice, clinical-grade, Immunologic diseases. Allergy, RC581-607
Abstract

Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing in vitro expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 109 to 1011 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment. Consequently, we developed and optimized a novel method for the efficient production of large numbers of GMP-grade, gene-modified TIL for the treatment of patients with ACT. The chemokine receptor CXCR2 was used as the gene of interest for methodology development. The optimized procedure is currently used in the production of gene-modified TIL for two clinical trials for the treatment of metastatic melanoma at MD Anderson Cancer Center.

Published
2017
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2. Supplementary Methods from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Author

Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi

Abstract

PDF file - 115K

Published
2023
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3. Supplementary Figure 1 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 473K, (A) Frequencies of IL-1α and IL-1β staining at different disease stages. Sections of a melanoma progression tissue array stained with antibodies specific for IL-1α or IL-1β and visualized by Vector-red immunostaining. Red color indicates positive staining for (C-E) IL-1α or (G-I) IL-1β in representative primary and metastatic tumors. (J) IL-1α or (K) IL-1β from stage 3 lymph node metastasis of tumors with (red) or without (black) the BRAF V600E mutation. Scores indicates the product of the intensity of signal (0-3) and frequency (0-100) of immunoreactive cells. (L) Presence or absence of IL-1α or IL-1β in melanoma cell lines with known BRAF mutational status. Asterisks, in house, or references (ref.) indicate the source of mutational analysis, (first) and the source of the IL-1 analysis (first and last respectively). Methods of BRAF mutational analysis are indicated by P, pyrosequencing; S, Sanger sequencing; Q, sequenome. Bold text indicates cell lines used in this study.

Published
2023
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4. Supplementary Figure 3 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 212K, (A) H&E staining of representative, A375 human xenograft tumor sections excised from NOD/SCID mice. Prior to excision, mice with established tumors were treated for 3 days with either PLX4720 or DMSO vehicle control. Magnification: 4x. (B) RT-PCR analysis of human IL1α, IL1β, IL-8, GRO-α, PD-L1, and PD-L2 transcripts derived from A375 xenografts shown in (A). Data show the average of 3 mice per group, and are representative of 3 separate experiments.

Published
2023
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5. Supplementary Figure 5 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 78K, (A) Dose titration curve showing surface expression of PD-L1 on TAFs as measured by flow cytometry 18 hours following exposure to titrated doses of IL-1α or IL-1β. (B) Time course experiment assessing surface expression of PD-L1 by flow cytometry following exposure of TAFs to 1 ng/ml IL-1β.

Published
2023
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6. Supplementary Figure Legend from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 94K.

Published
2023
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7. Data from Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome

Author

Chantale Bernatchez, Rodabe N. Amaria, Patrick Hwu, Rameen Beroukhim, Carlos A. Torres-Cabala, Laszlo G. Radvanyi, Jennifer A. Wargo, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Suzanne Cain, Michael K. Wong, Hussein Tawbi, Isabella C. Glitza, Adi Diab, Michael A. Davies, Sapna P. Patel, Wen-Jen Hwu, Portia G. Velasquez, Chantell M. Farinas, Carol Vaughn, Destiny Joy Carpio, Vruti Patel, Rahmatu Mansaray, Seth Wardell, Christopher L. Toth, Audrey M. Gonzalez, Renjith Ramachandran, René J. Tavera, Shawne T. Thorsen, Esteban Flores, Arely Wahl, Ankit Bhatta, Donastas Sakellariou-Thompson, Young Uk Kim, Scott E. Woodman, Jason Roszik, Orenthial J. Fulbright, Tatiana Karpinets, Caitlin Creasy, Yuzhong Jeff Meng, Kenneth R. Hess, Cara Haymaker, and Marie-Andrée Forget

Abstract

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence.Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated.Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome.Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

Published
2023
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8. Supplementary Figure 4 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 188K, Tumor-associated fibroblasts (TAF) cultures were derived from three separate metastatic melanoma biopsies from three distinct anatomical sites: lymph node, lung and soft tissue. Cultured TAFs were exposed overnight to IL-1α, and treated and untreated cells were subjected to Affymetrix gene expression analysis. (A) Heatmap displaying the 197 most differentially expressed genes selected at FDR 0.01. Relative expression values are indicated by the color bar. (B) Gene set enrichment analysis of IL-1α-treated TAFs demonstrates a strong correlation with gene sets previously identified to be associated with NF-kappaB upregulation and the interferon response. (C) Heatmap showing IL-1α induced expression of nine genes previously reported to be associated with T-cell suppression.

Published
2023
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9. Supplementary Table 5 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Author

Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi

Abstract

PDF file - 77K, Long term changes in the persistence of TCR Vβ clonotypes in the blood following TIL adoptive transfer in representative responding patients

Published
2023
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10. Data from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

Purpose: In this study, we assessed the specific role of BRAF(V600E) signaling in modulating the expression of immune regulatory genes in melanoma, in addition to analyzing downstream induction of immune suppression by primary human melanoma tumor-associated fibroblasts (TAF).Experimental Design: Primary human melanocytes and melanoma cell lines were transduced to express WT or V600E forms of BRAF, followed by gene expression analysis. The BRAF(V600E) inhibitor vemurafenib was used to confirm targets in BRAF(V600E)-positive melanoma cell lines and in tumors from melanoma patients undergoing inhibitor treatment. TAF lines generated from melanoma patient biopsies were tested for their ability to inhibit the function of tumor antigen-specific T cells, before and following treatment with BRAF(V600E)-upregulated immune modulators. Transcriptional analysis of treated TAFs was conducted to identify potential mediators of T-cell suppression.Results: Expression of BRAF(V600E) induced transcription of interleukin 1 alpha (IL-1α) and IL-1β in melanocytes and melanoma cell lines. Further, vemurafenib reduced the expression of IL-1 protein in melanoma cell lines and most notably in human tumor biopsies from 11 of 12 melanoma patients undergoing inhibitor treatment. Treatment of melanoma-patient–derived TAFs with IL-1α/β significantly enhanced their ability to suppress the proliferation and function of melanoma-specific cytotoxic T cells, and this inhibition was partially attributable to upregulation by IL-1 of COX-2 and the PD-1 ligands PD-L1 and PD-L2 in TAFs.Conclusions: This study reveals a novel mechanism of immune suppression sensitive to BRAF(V600E) inhibition, and indicates that clinical blockade of IL-1 may benefit patients with BRAF wild-type tumors and potentially synergize with immunotherapeutic interventions. Clin Cancer Res; 18(19); 5329–40. ©2012 AACR.

Published
2023
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11. Supplementary Figure 2 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 303K, IL-1α production is reduced by BRAF knockdown shRNA expression in melanoma cells. IL-1α staining in WM793 melanoma cells transduced with scrambled shRNA vector, BRAF targeting shRNA vectors, or untranduced as indicated. Expression of shRNA is indicated by coexpression of RFP (x-axis) and is induced by treatment with 2 ug/mL Doxycycline (DOX) (Lower). Cells were treated with DOX for one week prior to flow analysis by intracellular staining for IL-1α.

Published
2023
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12. Supplementary Table 1 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Author

Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi

Abstract

PDF file - 58K, Demographics and clinical characteristics of enrolled patients

Published
2023
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13. Supplementary Figures 1 - 7 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Author

Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi

Abstract

PDF file - 1856K, Fig. S1. Schema of TIL adoptive cell therapy clinical trial; Fig. S2. Recovery of total white blood cell counts (WBC), absolute lymphocyte counts (ALC), and absolute neutrophil counts (ANC) during adoptive transfer TIL therapy in 31 treated patients; Fig. S3. Durable partial response of an intrathoracic melanoma mass near the aorta and heart in one patient at 6 weeks and 18 months after TIL infusion; Figure S4. Kaplan-Meier curves of overall survival and progression-free survival for all 31 treated patients; Figure S5. Kaplan-Meier curves of landmark-based overall survival and progression-free survival for irRC responding and non-responding TIL-treated patients; Fig. S6. Change in tumor burden over the first 20-22 months following TIL transfer therapy in responders and non-responders; Fig. S7. Box and whisker plot showing that telomere length of infused TIL was not significantly different between responders and non-responders

Published
2023
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14. Supplementary Figure and Supplementary Tables from Prospective Analysis of Adoptive TIL Therapy in Patients with Metastatic Melanoma: Response, Impact of Anti-CTLA4, and Biomarkers to Predict Clinical Outcome

Author

Chantale Bernatchez, Rodabe N. Amaria, Patrick Hwu, Rameen Beroukhim, Carlos A. Torres-Cabala, Laszlo G. Radvanyi, Jennifer A. Wargo, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Suzanne Cain, Michael K. Wong, Hussein Tawbi, Isabella C. Glitza, Adi Diab, Michael A. Davies, Sapna P. Patel, Wen-Jen Hwu, Portia G. Velasquez, Chantell M. Farinas, Carol Vaughn, Destiny Joy Carpio, Vruti Patel, Rahmatu Mansaray, Seth Wardell, Christopher L. Toth, Audrey M. Gonzalez, Renjith Ramachandran, René J. Tavera, Shawne T. Thorsen, Esteban Flores, Arely Wahl, Ankit Bhatta, Donastas Sakellariou-Thompson, Young Uk Kim, Scott E. Woodman, Jason Roszik, Orenthial J. Fulbright, Tatiana Karpinets, Caitlin Creasy, Yuzhong Jeff Meng, Kenneth R. Hess, Cara Haymaker, and Marie-Andrée Forget

Abstract

Supplementary figures and tables

Published
2023
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15. Supplementary Table 2 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Author

Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi

Abstract

PDF file - 69K, Derivation of the irRC best overall score

Published
2023
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16. Supplementary Table 3 - 4 from Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

Author

Patrick Hwu, Audrey Gonzalez, Seth Wardell, Renjith Ramachandran, Christopher Toth, Orenthial J. Fulbright, Rahmatu Mansaray, Michael A. Davies, Janice N. Cormier, Richard Royal, Anthony Lucci, Jeffrey E. Gershenwald, Jeffrey E. Lee, Merrick I. Ross, Sapna Patel, Wen-Jen Hwu, Agop Bedikian, Jade Homsi, Kevin Kim, Nicholas Papadopoulos, Victor Prieto, Elizabeth Shpall, John D. McMannis, Valen E. Johnson, Michelle Glass, Gladys Alvarado, Sandy Mahoney, Gregory Lizee, Richard Wu, Jessica Chacon, Priscilla Miller, Patricia S. Fox, Minying Zhang, Chantale Bernatchez, and Laszlo G. Radvanyi

Abstract

PDF file - 76k, Table S3. Associations between categorical patient variables and clinical response; Table S4. Associations between continuous variables and clinical response

Published
2023
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17. Supplementary Figure 6 from Oncogenic BRAF(V600E) Promotes Stromal Cell-Mediated Immunosuppression Via Induction of Interleukin-1 in Melanoma

Author

Gregory Lizée, Patrick Hwu, Jennifer A. Wargo, Michael A. Davies, Richard E. Davis, Laszlo G. Radvanyi, Elizabeth Grimm, Suhendan Ekmekcioglu, Chantale Bernatchez, Richard W. Joseph, Min Zhang, Yufeng Li, Dennie T. Frederick, Zachary A. Cooper, Minying Zhang, Chengwen Liu, Seth Wardell, Mayra Whittington, Tania G. Rodríguez-Cruz, Shujuan Liu, and Jahan S. Khalili

Abstract

PDF file, 99K, Four separate TAF lines were derived from human melanoma tumor biopsies and exposed overnight to recombinant human IL-1α (1 ng/ml) or IFN-γ (500 U/ml). TAFs were then stained using antibodies specific for PD-L1 and PD-L2, and analyzed for surface expression by flow cytometry.

Published
2023
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18. Abstract 2746: Preclinical activity and manufacturing feasibility of genetically modified PDCD-1 knockout (KO) tumor-infiltrating lymphocyte (TIL) cell therapy

Author

Arvind Natarajan, Anand Veerapathran, Adrian Wells, Kenneth Onimus, Marcus Machin, Seth Wardell, Jamie L. Blauvelt, Madan Jagasia, and Rafael Cubas

Subjects
Cancer Research, Oncology
Abstract

Background: Adoptive cell therapy with autologous TIL has demonstrated an objective response rate (ORR) of 36% in the post-immune checkpoint inhibitor (ICI) setting in patients (pts) with advanced/unresectable melanoma (Sarnaik JCO 2021), while in ICI-naïve pts who received early-line combination of TIL and pembrolizumab, the ORR was 60%, with a 30% CR rate (O’Malley SITC 2021). Although effective, anti-PD-1 therapy is limited by poor penetration into the tumor, internalization, and endocytic clearance, in contrast with TIL, which overcome this inherent limitation. PDCD-1 gene inactivation (PD-1 KO) may enhance TIL cell therapy efficacy in the post-ICI setting and abrogate the need for systemic anti-PD-1 therapy in ICI-naïve pts. In preclinical studies, PD-1 KO TIL maintain robust effector function and phenotypic markers indicative of functional TIL (Ritthipichai ESMO 2020). We describe preclinical activity, clinical-scale manufacturing process development, and characterization of IOV-4001, an autologous PD-1 KO TIL cell product. Methods: hIL-2 NOG mice engrafted with melanoma tumor cells received adoptive transfer of autologous PD-1 KO TIL (developed with TALEN® gene editing technology in collaboration with Cellectis), mock TIL (electroporation without TALEN), mock TIL + anti-PD-1 antibody, or no adoptive transfer (n=14 each). Tumor size was measured 2×/wk for 39 days. A 22-day clinical-scale manufacturing process was established, including pre-rapid expansion protocol (pre-REP), activation, electroporation, resting, and REP, for the generation of PD-1 KO TIL. Final PD-1 KO TIL product was characterized for total viable cells (TVC), purity (% viability), identity (% CD45+CD3+), and function (PD-1 KO efficiency). Results: Day 39 mean ± SEM tumor size (mm2) for mice treated with PD-1 KO TIL (6 ± 2.8) showed superior tumor control relative to mock TIL (26 ± 8.5, P Conclusions: Anti-tumor activity of PD-1 KO TIL was superior to mock TIL suggesting that endogenous PD-1 inhibition may confer a functional advantage to the TIL over an antibody combination. PD-1 KO TIL clinical manufacturing was feasible and the TIL product quality attributes and phenotype were acceptable; importantly, lack of complete PD-1 KO may spare other PD-1-dependent in vivo cellular functions. Together, these data support clinical investigation of IOV-4001, an autologous PD-1 KO TIL cell therapy. Citation Format: Arvind Natarajan, Anand Veerapathran, Adrian Wells, Kenneth Onimus, Marcus Machin, Seth Wardell, Jamie L. Blauvelt, Madan Jagasia, Rafael Cubas. Preclinical activity and manufacturing feasibility of genetically modified PDCD-1 knockout (KO) tumor-infiltrating lymphocyte (TIL) cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2746.

Published
2022
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19. Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma

Author

Young Uk Kim, Marie Andrée Forget, Rahmatu Mansaray, Rene J. Tavera, Arely Wahl, Patrick Hwu, Seth Wardell, Esteban Flores, Dan S. Gombos, Audrey M. Gonzalez, Laszlo Radvanyi, Orenthial J. Fulbright, Christopher Toth, Donastas Sakellariou-Thompson, Rodabe N. Amaria, Renjith Ramachandran, Caitlin Creasy, Cara Haymaker, Sapna Pradyuman Patel, Ankit Bhatta, Chantale Bernatchez, and Shawne T. Thorsen

Subjects
Male, Uveal Neoplasms, 0301 basic medicine, Interleukin 2, Cancer Research, Skin Neoplasms, T-Lymphocytes, T cell, medicine.medical_treatment, Immunology, chemical and pharmacologic phenomena, Immunotherapy, Adoptive, Article, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Melanoma, Pharmacology, Tumor-infiltrating lymphocytes, business.industry, CD137, hemic and immune systems, Immunotherapy, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cutaneous melanoma, Cancer research, Interleukin-2, Female, business, CD8, medicine.drug
Abstract

In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in

Published
2018
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20. Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome

Author

Carlos A. Torres-Cabala, Jeffrey E. Gershenwald, Jason Roszik, Vruti Patel, Wen-Jen Hwu, Anthony Lucci, M. I. Ross, Arely Wahl, Orenthial J. Fulbright, Yuzhong Jeff Meng, Christopher Toth, Tatiana Karpinets, Cara Haymaker, Chantell M. Farinas, Sapna Pradyuman Patel, Adi Diab, Caitlin Creasy, Patrick Hwu, Renjith Ramachandran, Jeffrey E. Lee, Isabella C. Glitza, Ankit Bhatta, Destiny Joy Carpio, Rodabe N. Amaria, Esteban Flores, Suzanne Cain, Michael K. Wong, Laszlo Radvanyi, Rameen Beroukhim, Portia G. Velasquez, Hussein Abdul-Hassan Tawbi, Chantale Bernatchez, Carol Vaughn, Shawne T. Thorsen, Marie Andrée Forget, Michael A. Davies, Young Uk Kim, Seth Wardell, Janice N. Cormier, Scott E. Woodman, Jennifer A. Wargo, Rahmatu Mansaray, Richard E. Royal, Rene J. Tavera, Audrey M. Gonzalez, Kenneth R. Hess, and Donastas Sakellariou-Thompson

Subjects
0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Programmed Cell Death 1 Receptor, BTLA, chemical and pharmacologic phenomena, Immunotherapy, Adoptive, Article, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, Internal medicine, medicine, Combined Modality Therapy, Humans, CTLA-4 Antigen, Progression-free survival, Neoplasm Metastasis, Melanoma, Aged, business.industry, Interleukin-9, Cancer, hemic and immune systems, Neoplasms, Second Primary, Immunotherapy, Middle Aged, medicine.disease, Progression-Free Survival, Blockade, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Female, business
Abstract

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Patients and Methods: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival, and progression-free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint-naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4-naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA4 naïve patients, but not in anti-CTLA4 refractory patients. Baseline serum levels of IL9 predicted response to TIL ACT, while TIL persistence, tumor recognition, and mutation burden did not correlate with outcome. Conclusions: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL9 levels can potentially serve as a predictive tool to select the appropriate sequence of immunotherapies. Clin Cancer Res; 24(18); 4416–28. ©2018 AACR.

Published
2018

21. 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
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22. Genetic and molecular characterization of uveal melanoma cell lines

Author

Jahan Khalili, Chantale Bernatchez, Katherine Stempke-Hale, M. Mert Sozen, Seth Wardell, Xiaoxing Yu, Scott E. Woodman, Klaus G. Griewank, and Boris C. Bastian

Subjects
Regulation of gene expression, Mutation, GNA11, Melanoma, Dermatology, Biology, medicine.disease, medicine.disease_cause, eye diseases, General Biochemistry, Genetics and Molecular Biology, Pathogenesis, Oncology, Cell culture, medicine, Cancer research, neoplasms, Gene, GNAQ
Abstract

The recent identification of frequent activating mutations in GNAQ or GNA11 in uveal melanoma provides an opportunity to better understand the pathogenesis of this melanoma subtype and to develop rational therapeutics to target the cellular effects mediated by these mutations. Cell lines from uveal melanoma tumors are an essential tool for these types of analyses. We report the mutation status of relevant melanoma genes, expression levels of proteins of interest, and DNA fingerprinting of a panel of uveal melanoma cell lines used in the research community.

Published
2012
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23. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

Author

Kevin B. Kim, Michelle R. Glass, Sapna Pradyuman Patel, Jessica Ann Chacon, John McMannis, Renjith Ramachandran, Sandy Mahoney, Gladys Alvarado, Elizabeth J. Shpall, Valen E. Johnson, Wen-Jen Hwu, Patrick Hwu, Agop Y. Bedikian, Rahmatu Mansaray, Seth Wardell, Jeffrey E. Gershenwald, Janice N. Cormier, Christopher Toth, Richard Wu, Jeffrey E. Lee, Orenthial J. Fulbright, Patricia S. Fox, Laszlo Radvanyi, Priscilla W. Miller, Michael A. Davies, Richard E. Royal, Minying Zhang, Audrey M. Gonzalez, Gregory Lizée, Chantale Bernatchez, Victor G. Prieto, Anthony Lucci, Jade Homsi, Nicholas Papadopoulos, and Merrick I. Ross

Subjects
Interleukin 2, Male, Cancer Research, Skin Neoplasms, medicine.medical_treatment, Population, BTLA, chemical and pharmacologic phenomena, Immunotherapy, Adoptive, Transplantation, Autologous, Disease-Free Survival, Article, Cell therapy, Medicine, Humans, education, Melanoma, Cells, Cultured, education.field_of_study, business.industry, Remission Induction, Immunotherapy, Middle Aged, Telomere, medicine.disease, Combined Modality Therapy, Survival Analysis, Lymphocyte Subsets, Tumor Burden, Transplantation, Treatment Outcome, Oncology, Immunology, Cancer research, Interleukin-2, Female, business, CD8, medicine.drug, T-Lymphocytes, Cytotoxic
Abstract

Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. Clin Cancer Res; 18(24); 6758–70. ©2012 AACR.

Published
2012

24. Intranasal immunization with synthetic peptides corresponding to the E6 and E7 oncoproteins of human papillomavirus type 16 induces systemic and mucosal cellular immune responses and tumor protection

Author

Pallavi R. Manuri, Ashok K. Chopra, Rose Reisenauer, Dakshyani Lomada, Pramod N. Nehete, Bharti P. Nehete, Amy N. Courtney, K. Jagannadha Sastry, Ratish Gambhira, and Seth Wardell

Subjects
Cellular immunity, Cholera Toxin, medicine.medical_treatment, T cell, Papillomavirus E7 Proteins, Molecular Sequence Data, Uterine Cervical Neoplasms, Biology, Article, Interferon-gamma, Mice, Immune system, medicine, Animals, Amino Acid Sequence, Papillomavirus Vaccines, Immunity, Mucosal, Administration, Intranasal, Vaccines, Synthetic, General Veterinary, General Immunology and Microbiology, Public Health, Environmental and Occupational Health, Oncogene Proteins, Viral, Peptide Fragments, Vaccination, Mice, Inbred C57BL, Repressor Proteins, CTL, Infectious Diseases, medicine.anatomical_structure, Immunization, Immunology, Molecular Medicine, Female, Adjuvant, CD8, T-Lymphocytes, Cytotoxic
Abstract

The E6 and E7 oncoproteins of the high-risk HPV type16 represent ideal targets for HPV vaccine development, they being consistently expressed in cervical cancer lesions. Since HPV-16 is primarily transmitted through genital mucosal route, mucosal immune responses constitute an essential feature for vaccination strategies against HPV-associated lesions. We present here evidence showing that mucosal immunization of mice by the intranasal route with a mixture of peptides E7(44-62) and E6(43-57) from the E7 and E6 oncoproteins of HPV-16, respectively, using a mutant cholera toxin adjuvant (CT-2*), primed strong antigen-specific cellular immune responses in systemic and mucosal tissues. Significant levels of IFN-gamma production by both CD4 and CD8 cells were observed along with CTL responses that were effective against both peptide-pulsed targets as well as syngeneic tumor cells (TC-1) expressing the cognate E6 and E7 proteins. Furthermore, mice immunized with the peptide mixture and CT-2* effectively resisted TC-1 tumor challenge. These results together with our earlier observations that T cell responses to these peptides correlate with recurrence-free survival in women after ablative treatment for HPV-associated cervical intraepithelial neoplasia, support the potential of these E6 and E7 peptides for inclusion in vaccine formulations.

Published
2006

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