851 results on '"Jeffrey, Schlom"'
Search Results
52. 445 Blockade of the inhibitory collagen receptor LAIR-1 with NC410, a LAIR2-Fc fusion protein, enhances anti-tumor activity of the bifunctional fusion protein bintrafusp alfa
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Jeffrey Schlom, Claudia Palena, Lucas Horn, Linjie Tian, Dallas Flies, Linda Liu, and Solomon Langermann
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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53. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies
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Renee N Donahue, Jeffrey Schlom, James L Gulley, Ravi A Madan, Caroline Jochems, Elizabeth Lamping, Julius Strauss, Marijo Bilusic, Fatima Karzai, Christian S Hinrichs, Edward McClay, Jennifer L Marté, Lisa M Cordes, Andrew Hill, Byoung Chul Cho, Sébastien Salas, Laureen S Ojalvo, P Alexander Rolfe, Margaret E Gatti-Mays, Jason M Redman, Houssein A Sater, Andrea Burmeister, and Genevieve Jehl more...
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.Methods In these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.Results As of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.Conclusion Bintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers. more...
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- 2020
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54. Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management
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Renee N Donahue, Jeffrey Schlom, James L Gulley, Lisa Cordes, Jennifer L Marté, and Nicole J Toney
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background The risk–benefit calculation for corticosteroid administration in the management of COVID-19 is complex and urgently requires data to inform the decision. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with poor prognosis in both COVID-19 and cancer. Investigating NLR as an inflammatory marker and lymphocyte levels as a critical component of antiviral immunity may inform the dilemma of reducing toxic hyperinflammation while still maintaining effective antiviral responses.Methods We performed a retrospective analysis of NLR, absolute neutrophil counts (ANCs) and absolute lymphocyte counts (ALCs) in patients with cancer enrolled in immunotherapy trials who received moderate-dose to high-dose corticosteroids. We compared paired presteroid and available poststeroid initiation values daily during week 1 and again on day 14 using the Wilcoxon signed-rank test. Associated immune subsets by flow cytometry were included where available.Results Patients (n=48) with a variety of solid tumors received prednisone, methylprednisolone, or dexamethasone alone or in combination in doses ranging from 20 to 190 mg/24 hours (prednisone equivalent). The median NLR prior to steroid administration was elevated at 5.0 (range: 0.9–61.2). The corresponding median ANC was 5.1 K/µL (range: 2.03–22.31 K/µL) and ALC was 1.03 K/µL (0.15–2.57 K/µL). One day after steroid administration, there was a significant transient drop in median ALC to 0.54 K/µL (p=0.0243), driving an increase in NLR (median 10.8, p=0.0306). Relative lymphopenia persisted through day 14 but was no longer statistically significant. ANC increased steadily over time, becoming significant at day 4 (median: 7.31 K/µL, p=0.0171) and remaining significantly elevated through day 14. NLR was consistently elevated after steroid initiation, significantly at days 1, 7 (median: 8.2, p=0.0272), and 14 (median: 15.0, p=0.0018). Flow cytometry data from 11 patients showed significant decreases in activated CD4 cells and effector memory CD8 cells.Conclusions The early drop in ALC with persistent lymphopenia as well as the prolonged ANC elevation seen in response to corticosteroid administration are similar to trends associated with increased mortality in several coronavirus studies to include the current SARS-CoV-2 pandemic. The affected subsets are essential for effective antiviral immunity. This may have implications for glucocorticoid therapy for COVID-19. more...
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- 2020
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55. A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in Metastatic Medullary Thyroid Cancer
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Jaydira Del Rivero, Renee N. Donahue, Jennifer L. Marté, Ann W. Gramza, Marijo Bilusic, Myrna Rauckhorst, Lisa Cordes, Maria J. Merino, William L. Dahut, Jeffrey Schlom, James L. Gulley, and Ravi A. Madan more...
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medullary thyroid cancer ,CEA ,calcitonin ,immunotherapy ,PD-L1 inhibitor ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC. more...
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- 2020
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56. Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells
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Yvette Robbins, Sarah Greene, Jay Friedman, Paul E Clavijo, Carter Van Waes, Kellsye P Fabian, Michelle R Padget, Houssein Abdul Sater, John H Lee, Patrick Soon-Shiong, James Gulley, Jeffrey Schlom, James W Hodge, and Clint T Allen more...
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NK cells ,chimerica antigen receptor ,PD-L1 ,syngeneic ,myeloid ,xenograft ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted. more...
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- 2020
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57. Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances
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Jeffrey Schlom, James L Gulley, Claudia Palena, Caroline Jochems, Julius Strauss, Hanne Lind, and Sofia R Gameiro
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immunosuppressive entities in the tumor microenvironment (TME) remain a major impediment to immunotherapeutic approaches for a majority of patients with cancer. While the immunosuppressive role of transforming growth factor-β (TGF-β) in the TME is well known, clinical studies to date with anti-TGF-β agents have led to limited success. The bifunctional agent bintrafusp alfa (previously designated M7824) has been developed in an attempt to address this issue. Bintrafusp alfa consists of an IgG1 targeting programmed death ligand 1 (PD-L1) moiety fused via peptide linkers to the extracellular domain of two TGF-β receptor II molecules designed to ‘trap’ TGF-β in the TME. This agent is able to bring the TGF-β trap to the TME via its anti-PD-L1 component, thus simultaneously attacking both the immunosuppressive PD-L1 and TGF-β entities. A number of preclinical studies have shown bintrafusp alfa capable of (1) preventing or reverting TGF-β-induced epithelial-mesenchymal transition in human carcinoma cells; this alteration in tumor cell plasticity was shown to render human tumor cells more susceptible to immune-mediated attack as well as to several chemotherapeutic agents; (2) altering the phenotype of natural killer and T cells, thus enhancing their cytolytic ability against tumor cells; (3) mediating enhanced lysis of human tumor cells via the antibody-dependent cell-mediated cytotoxicity mechanism; (4) reducing the suppressive activity of Treg cells; (5) mediating antitumor activity in numerous preclinical models and (6) enhancing antitumor activity in combination with radiation, chemotherapy and several other immunotherapeutic agents. A phase I clinical trial demonstrated a safety profile similar to other programmed cell death protein 1 (PD-1)/PD-L1 checkpoint inhibitors, with objective and durable clinical responses. We summarize here preclinical and emerging clinical data in the use of this bispecific and potentially multifunctional agent. more...
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- 2020
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58. Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity
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Jeffrey Schlom, Claudia Palena, Kristen Fousek, Zhen Su, Duane H Hamilton, Hanne Lind, Lucas A Horn, Jeffrey Riskin, Heidi A Hempel, Kristen K McCampbell, Dean Y Maeda, and John A Zebala
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Despite the success of immune checkpoint blockade therapy in the treatment of certain cancer types, only a small percentage of patients with solid malignancies achieve a durable response. Consequently, there is a need to develop novel approaches that could overcome mechanisms of tumor resistance to checkpoint inhibition. Emerging evidence has implicated the phenomenon of cancer plasticity or acquisition of mesenchymal features by epithelial tumor cells, as an immune resistance mechanism.Methods Two soluble factors that mediate tumor cell plasticity in the context of epithelial-mesenchymal transition are interleukin 8 (IL-8) and transforming growth factor beta (TGF-β). In an attempt to overcome escape mechanisms mediated by these cytokines, here we investigated the use of a small molecule inhibitor of the IL-8 receptors CXCR1/2, and a bifunctional agent that simultaneously blocks programmed death ligand 1 (PD-L1) and traps soluble TGF-β.Results We demonstrate that simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells, significantly enhancing T-cell infiltration and activation in tumors, and leading to improved antitumor activity.Conclusions This study highlights the potential benefit of combined blockade of CXCR1/2 and TGF-β signaling for modulation of tumor plasticity and potential enhancement of tumor responses to PD-L1 blockade. The data provide rationale for the evaluation of this novel approach in the clinic. more...
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- 2020
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59. Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer
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Renee N Donahue, Jeffrey Schlom, James L Gulley, Christopher R Heery, Ravi A Madan, Marijo Bilusic, Fatima Karzai, Houssein Abdul Sater, Jennifer L Marté, Beatriz Walter-Rodriguez, Seth M Steinberg, Guinevere Chun, Stephanie A Harmon, Ismail Baris Turkbey, Peter L Choyke, William L Dahut, and Peter A Pinto more...
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Clinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site.Methods An open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1.Results Of 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136–317/mm² vs 69–284/mm²; p=0.0249; median ratio 1.20; IQR 0.64–2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123–500/mm² vs 85–256/mm²; p=0.042; median ratio 1.44; IQR 0.59–4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91–175/mm² vs 83–163/mm²; p=0.036; median ratio 1.25; IQR 0.88–2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated.Conclusion Neoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.Trial registration number NCT02153918. more...
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- 2020
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60. Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist
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Jeffrey Schlom, Sofia R Gameiro, Karin M Knudson, Kristin C Hicks, and Yohei Ozawa
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Anti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two αPD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+αPD-L1 combination.Methods The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+αPD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN).Results We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+αPD-L1. Compared with N-803+αPD-L1, N-809 enhanced natural killer (NK) and CD8+ T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8+ T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8+ T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+αPD-L1, N-809 reduced immunosuppressive regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME.Conclusions Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8+ T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including Treg, M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma. more...
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- 2020
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61. Overcoming hypoxia-induced functional suppression of NK cells
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Jeffrey Schlom, James W Hodge, Shahrooz Rabizadeh, Patrick Soon-Shiong, Fabiola Cecchi, Todd Hembrough, Benjamin Wolfson, Kristen Solocinski, Michelle R Padget, Kellsye P Fabian, and Stephen C Benz
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Natural killer (NK) cells are immune cells capable of killing virally infected cells and tumor cells without the need for antigen stimulation. Tumors, however, can create a suppressive microenvironment that decreases NK function. A feature of many tumors is hypoxia (low oxygen perfusion), which has been previously shown to decrease NK function. A high affinity NK (haNK) cell has been engineered to express a high affinity CD16 receptor as well as internal interleukin (IL)-2 for increased antibody-dependent cellular cytotoxicity (ADCC) and activation, respectively. We sought to investigate the tolerance of NK cells versus haNK cells to hypoxia.Methods We exposed healthy donor (HD) NK and X-irradiated haNK cells to normoxia (20% oxygen) as well as hypoxia (0% oxygen) and investigated their ability to kill prostate, breast and lung tumor cell lines after 5 hours. We also used monoclonal antibodies cetuximab (anti-EGFR) or avelumab (antiprogrammed death-ligand 1) to investigate the effects of hypoxia on NK ADCC. Genomic and proteomic analyzes were done to determine the effect of hypoxia on the expression of factors important to NK cell function.Results While HD NK cell cytolytic abilities were markedly and significantly impaired under hypoxic conditions, haNK cells maintained killing capacity under hypoxic conditions. NK killing, serial killing and ADCC were maintained under hypoxia in haNK cells. IL-2 has been previously implicated in serial killing and perforin regeneration and thus the endogenous IL-2 produced by haNK cells is likely a driver of the maintained killing capacity of haNK cells under hypoxic conditions. Activation of signal transducer and activator of transcription 3 (STAT3) is not seen in haNKs under hypoxia but is significant in HD NK cells. Pharmaceutical activation of STAT3 in haNKs led to reduced killing, implicating active STAT3 in reduced NK cell function.Conclusions In contrast to HD NK cells, haNK cells are resistant to acute hypoxia. The potent cytolytic function of haNK cells was maintained in an environment comparable to what would be encountered in a tumor. The data presented here provide an additional mechanism of action for haNK cells that are currently being evaluated in clinical trials for several tumor types. more...
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- 2020
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62. PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations
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Jeffrey Schlom, James W Hodge, Clint T. Allen, Shahrooz Rabizadeh, Patrick Soon-Shiong, John H. Lee, Renee N. Donahue, Kristen Solocinski, Michelle R Padget, Kellsye P Fabian, and Yvette Robbins
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Although immune checkpoint inhibitors have revolutionized cancer treatment, clinical benefit with this class of agents has been limited to a subset of patients. Hence, more effective means to target tumor cells that express immune checkpoint molecules should be developed. For the first time, we report a novel natural killer (NK) cell line, programmed death-ligand 1 (PD-L1) targeting high-affinity natural killer (t-haNK), which was derived from NK-92 and was engineered to express high-affinity CD16, endoplasmic reticulum-retained interleukin (IL)-2, and a PD-L1-specific chimeric antigen receptor (CAR). We show that PD-L1 t-haNK cells also retained the expression of native NK receptors and carried a high content of granzyme and perforin granules.Methods NanoString, flow cytometry, and immunofluorescence analyses were performed to characterize the phenotype of irradiated PD-L1 t-haNK cells. In vitro PD-L1 t-haNK cell activity against cancer cell lines and human peripheral blood mononuclear cells (PBMCs) was determined via flow-based and 111In-release killing assays. The antitumor effect of PD-L1 t-haNK cells in vivo was investigated using MDA-MB-231, H460, and HTB1 xenograft models in NOD-scid IL2Rgammanull (NSG) mice. Additionally, the antitumor effect of PD-L1 t-haNK cells, in combination with anti-PD-1 and N-803, an IL-15 superagonist, was evaluated using mouse oral cancer 1 syngeneic model in C57BL/6 mice.Results We show that PD-L1 t-haNK cells expressed PD-L1-targeting CAR and CD16, retained the expression of native NK receptors, and carried a high content of granzyme and perforin granules. In vitro, we demonstrate the ability of irradiated PD-L1 t-haNK cells to lyse 20 of the 20 human cancer cell lines tested, including triple negative breast cancer (TNBC) and lung, urogenital, and gastric cancer cells. The cytotoxicity of PD-L1 t-haNK cells was correlated to the PD-L1 expression of the tumor targets and can be improved by pretreating the targets with interferon (IFN)-γ. In vivo, irradiated PD-L1 t-haNK cells inhibited the growth of engrafted TNBC and lung and bladder tumors in NSG mice. The combination of PD-L1 t-haNK cells with N-803 and anti-PD-1 antibody resulted in superior tumor growth control of engrafted oral cavity squamous carcinoma tumors in C57BL/6 mice. In addition, when cocultured with human PBMCs, PD-L1 t-haNK cells preferentially lysed the myeloid-derived suppressor cell population but not other immune cell types.Conclusion These studies demonstrate the antitumor efficacy of PD-L1 t-haNK cells and provide a rationale for the potential use of these cells in clinical studies. more...
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- 2020
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63. Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine
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Jeffrey Schlom, Samuel T Pellom, Caroline Jochems, Claire Smalley Rumfield, and Y Maurice Morillon II
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background While prophylactic human papillomavirus (HPV) vaccines will certainly reduce the incidence of HPV-associated cancers, these malignancies remain a major health issue. PDS0101 is a liposomal-based HPV therapeutic vaccine consisting of the immune activating cationic lipid R-DOTAP and HLA-unrestricted HPV16 peptides that has shown in vivo CD8+ T cell induction and safety in a phase I study. In this report, we have employed the PDS0101 vaccine with two immune modulators previously characterized in preclinical studies and which are currently in phase II clinical trials. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domains of the transforming growth factor-β receptor type II (TGFβRII) fused to a human IgG1 monoclonal antibody blocking programmed cell death protein-1 ligand (PDL1), designed both as a checkpoint inhibitor and to bring the TGFβRII ‘trap’ to the tumor microenvironment (TME). NHS-interleukin-12 (NHS-IL12) is a tumor targeting immunocytokine designed to bring IL-12 to the TME and thus enhance the inflammatory Th1 response.Methods We employed TC-1 carcinoma (expressing HPV16 E6 and E7 and devoid of PDL1 expression) in a syngeneic mouse model in monotherapy and combination therapy studies to analyze antitumor effects and changes in immune cell types in the spleen and the TME.Results As a monotherapy, the PDS0101 vaccine generated HPV-specific T cells and antitumor activity in mice bearing HPV-expressing mEER oropharyngeal and TC-1 lung carcinomas. When used as a monotherapy in the TC-1 model, NHS-IL12 elicited antitumor effects as well as an increase in CD8+ T cells in the TME. When used as a monotherapy, bintrafusp alfa did not elicit antitumor effects or any increase in T cells in the TME. When all three agents were used in combination, maximum antitumor effects were observed, which correlated with increases in T cells and T-cell clonality in the TME.Conclusion These studies provide the rationale for the potential clinical use of combinations of agents that can (1) induce tumor-associated T-cell responses, (2) potentiate immune responses in the TME and (3) reduce immunosuppressive entities in the TME. more...
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- 2020
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64. The Use of a Humanized NSG-β2m−/− Model for Investigation of Immune and Anti-tumor Effects Mediated by the Bifunctional Immunotherapeutic Bintrafusp Alfa
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Y. Maurice Morillon, Claire Smalley Rumfield, Samuel T. Pellom, Ariana Sabzevari, Nicholas T. Roller, Lucas A. Horn, Caroline Jochems, Claudia Palena, John W. Greiner, and Jeffrey Schlom
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humanized mouse ,NSG-β2m−/− ,bintrafusp alfa ,immunotherapy ,TGF-β ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The lack of serial biopsies in patients with a range of carcinomas has been one obstacle in our understanding of the mechanism of action of immuno-oncology agents as well as the elucidation of mechanisms of resistance to these novel therapeutics. While much information can be obtained from studies conducted with syngeneic mouse models, these models have limitations, including that both tumor and immune cells being targeted are murine and that many of the immuno-oncology agents being evaluated are human proteins, and thus multiple administrations are hampered by host xenogeneic responses. Some of these limitations are being overcome by the use of humanized mouse models where human peripheral blood mononuclear cells (PBMC) are engrafted into immunosuppressed mouse strains. Bintrafusp alfa (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII to function as a TGF-β “trap” fused to a human IgG1 antibody blocking PD-L1. A phase I clinical trial of bintrafusp alfa showed promising anti-tumor efficacy in heavily pretreated advanced solid tumors, and multiple clinical studies are currently ongoing. There is still much to learn regarding the mechanism of action of bintrafusp alfa, including its effects on both human immune cells in the periphery and in the tumor microenvironment (TME), and any temporal effects upon multiple administrations. By using the NSG-β2m−/− mouse strain humanized with PBMC, we demonstrate here for the first time: (a) the effects of bintrafusp alfa administration on human immune cells in the periphery vs. the TME using three different human xenograft models; (b) temporal effects upon multiple administrations of bintrafusp alfa; (c) phenotypic changes induced in the TME, and (d) variations observed in the use of multiple different PBMC donors. Also discussed are the similarities and differences in the data thus far obtained employing murine syngeneic models, from clinical trials, and in the use of this humanized mouse model. The results described here may guide the future use of this agent or similar immunotherapy agents as monotherapies or in combination therapy studies. more...
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- 2020
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65. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations
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Fatima Karzai, David VanderWeele, Ravi A. Madan, Helen Owens, Lisa M. Cordes, Amy Hankin, Anna Couvillon, Erin Nichols, Marijo Bilusic, Michael L. Beshiri, Kathleen Kelly, Venkatesh Krishnasamy, Sunmin Lee, Min-Jung Lee, Akira Yuno, Jane B. Trepel, Maria J. Merino, Ryan Dittamore, Jennifer Marté, Renee N. Donahue, Jeffrey Schlom, Keith J. Killian, Paul S. Meltzer, Seth M. Steinberg, James L. Gulley, Jung-Min Lee, and William L. Dahut more...
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Durvalumab ,Olaparib ,mCRPC ,Abiraterone ,Enzalutamide ,Immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. Methods Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. Results Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. Conclusions Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. Trial registration ClinicalTrials.gov identifier: NCT02484404. more...
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- 2018
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66. Inhibition of WEE1 kinase and cell cycle checkpoint activation sensitizes head and neck cancers to natural killer cell therapies
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Jay Friedman, Megan Morisada, Lillian Sun, Ellen C. Moore, Michelle Padget, James W. Hodge, Jeffrey Schlom, Sofia R. Gameiro, and Clint T. Allen
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NK cells ,Resistance ,DNA damage checkpoint ,WEE1 kinase ,haNK cells ,KIL cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Natural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined. Methods Tumor cell sensitivity to cultured murine KIL and human high affinity NK (haNK) cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL cells into syngeneic mice was performed. Results Cultured murine KIL cells lyse murine oral cancer 2 (MOC2) cell targets more efficiently than freshly isolated peripheral murine NK cells. MOC2 sensitivity to granzyme B-dependent KIL cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M cell cycle checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer cell lines to direct lysis by haNK cells. Further, WEE1 kinase inhibition sensitized these cell lines to antibody-dependent cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab. Conclusions Tumor cell resistance to granzyme B-induced cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse cell cycle checkpoint activation and NK cellular therapies. more...
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- 2018
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67. Vaccines and Immunomodulators
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Jeffrey Schlom, Sofia R. Gameiro, Claudia Palena, and James L. Gulley
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- 2022
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68. Phase 1 trial of <scp>CV301</scp> in combination with <scp>anti‐PD</scp> ‐1 therapy in <scp>nonsquamous non‐small</scp> cell lung cancer
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Arun Rajan, Jhanelle E. Gray, Siddhartha Devarakonda, Ruemu Birhiray, Borys Korchin, Erika Menius, Renee N. Donahue, Jeffrey Schlom, and James L. Gulley
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Cancer Research ,Lung Neoplasms ,Nivolumab ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Animals ,Humans ,Middle Aged - Abstract
CV301, a poxviral-based vaccine, has been evaluated in a phase 1 clinical trial (NCT02840994) and shown to be safe and immunologically active (phase 1a). Preclinical data support a combination of CV301 with programmed death-1 inhibitors, which has been evaluated in the phase 1b part of this trial and is reported here. Patients with advanced nonsquamous non-small cell lung cancer (NSCLC) without actionable genomic alterations received two priming doses of modified vaccinia Ankara-BN-CV301 (MVA) 4 weeks apart, followed by boosting doses of fowlpox-CV301 (FPV) at increasing time intervals for a maximum of 17 doses in combination with nivolumab for cohort 1 (C1) and 15 doses in combination with pembrolizumab for cohort 2 (C2). The primary objective was evaluation of safety and tolerability. Between October 2017 and September 14, 2018, patients were enrolled (C1: 4; median age: 64 years). Mean treatment duration was 332 days in C1 and 289 days in C2. CTCAE ≥grade 3 adverse events (AEs) were observed in four (100%) patients in C1 and three (37.5%) patients in C2. There was one death on trial. Immune-related AEs (irAEs) fulfilling criteria for a dose-limiting toxicity included 1 case of pneumonitis. Among 11 evaluable patients, 1 (9%) had a complete response, 1 (9%) had a partial response and 9 (82%) had stable disease. We conclude that CV301 administered with PD-1 inhibitors is safe and clinically active in patients with advanced NSCLC. The frequency or severity of AEs is not increased, including irAEs for each component of the combination. more...
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- 2022
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69. The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex
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Caroline Jochems, Sarah R. Tritsch, Karin M. Knudson, Sofia R. Gameiro, Claire Smalley Rumfield, Samuel T. Pellom, Y. Maurice Morillon, Robby Newman, Warren Marcus, Christopher Szeto, Shahrooz Rabizadeh, Hing C. Wong, Patrick Soon-Shiong, and Jeffrey Schlom more...
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alt-803 ,n-803 ,il-15 ,n-809 ,anti-pd-l1 ,immunotherapy ,checkpoint inhibitor ,cytokine ,carcinoma ,adcc ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Here we describe a novel bifunctional fusion protein, designated N-809. This molecule comprises the IL-15/IL15Rα superagonist complex containing the Fc-domain of IgG1 (N-803, formerly designated as ALT-803) fused to two single chain anti-PD-L1 domains. The fully human IgG1 portion of the N-809 molecule was designed to potentially mediate antibody dependent cellular cytotoxicity (ADCC). The studies reported here show that N-809 has the same ability to bind PD-L1 as an anti-PD-L1 monoclonal antibody. RNAseq studies show the ability of N-809 to alter the expression of an array of genes of both CD4+ and CD8+ human T cells, and to enhance their proliferation; CD8+ T cells exposed to N-809 also have enhanced ability to lyse human tumor cells. An array of genes was differentially expressed in human natural killer (NK) cells following N-809 treatment, and there was increased expression of several surface activating receptors; there was, however, no increase in the expression of inhibitory receptors known to be upregulated in exhausted NK cells. N-809 also increased the cytotoxic potential of NK cells, as shown by increased expression of granzyme B and perforin. The lysis of several tumor cell types was increased when either NK cells or tumor cells were exposed to N-809. Similarly, the highest level of ADCC was seen when both NK cells (from donors or cancer patients) and tumor cells were exposed to N-809. These studies thus demonstrate the multi-functionality of this novel agent. more...
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- 2019
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70. Exploiting docetaxel-induced tumor cell necrosis with tumor targeted delivery of IL-12
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S. Elizabeth Franks, Ginette S. Santiago-Sanchez, Kellsye P. Fabian, Kristen Solocinski, Paul L. Chariou, Duane H. Hamilton, Joshua T. Kowalczyk, Michelle R. Padget, Sofia R. Gameiro, Jeffrey Schlom, and James W. Hodge more...
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Cancer Research ,Oncology ,Immunology ,Immunology and Allergy - Abstract
There is strong evidence that chemotherapy can induce tumor necrosis which can be exploited for the targeted delivery of immuno-oncology agents into the tumor microenvironment (TME). We hypothesized that docetaxel, a chemotherapeutic agent that induces necrosis, in combination with the bifunctional molecule NHS-IL-12 (M9241), which delivers recombinant IL-12 through specific targeting of necrotic regions in the tumor, would provide a significant antitumor benefit in the poorly inflamed murine tumor model, EMT6 (breast), and in the moderately immune-infiltrated tumor model, MC38 (colorectal). Docetaxel, as monotherapy or in combination with NHS-IL-12, promoted tumor necrosis, leading to the improved accumulation and retention of NHS-IL-12 in the TME. Significant antitumor activity and prolonged survival were observed in cohorts receiving docetaxel and NHS-IL-12 combination therapy in both the MC38 and EMT6 murine models. The therapeutic effects were associated with increased tumor infiltrating lymphocytes and were dependent on CD8+ T cells. Transcriptomics of the TME of mice receiving the combination therapy revealed the upregulation of genes involving crosstalk between innate and adaptive immunity factors, as well as the downregulation of signatures of myeloid cells. In addition, docetaxel and NHS-IL-12 combination therapy effectively controlled tumor growth of PD-L1 wild-type and PD-L1 knockout MC38 in vivo, implying this combination could be applied in immune checkpoint refractory tumors, and/or tumors regardless of PD-L1 status. The data presented herein provide the rationale for the design of clinical studies employing this combination or similar combinations of agents. more...
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- 2023
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71. Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer
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Ravi A Madan, Marijo Bilusic, Mark N Stein, Renee N Donahue, Philip M Arlen, Fatima Karzai, Elizabeth Plimack, Yu-Ning Wong, Daniel M Geynisman, Matthew Zibelman, Tina Mayer, Julius Strauss, Gang Chen, Myrna Rauckhorst, Sheri McMahon, Anna Couvillon, Seth Steinberg, William D Figg, William L Dahut, Jeffrey Schlom, and James L Gulley more...
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Cancer Research ,Oncology ,Clinical Trial Results - Abstract
Background Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. Methods This was a multicenter, randomized clinical trial comparing the ARA flutamide+/−PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. Results Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. Conclusion The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463) more...
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- 2023
72. Supplementary Data from Efficient Tumor Clearance and Diversified Immunity through Neoepitope Vaccines and Combinatorial Immunotherapy
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Duane H. Hamilton, Jeffrey Schlom, Kayvan Niazi, Patrick Soon-Shiong, Shahrooz Rabizadeh, John H. Lee, Lars Rohlin, Peter Ordentlich, Zhen Su, John Z. Sanborn, Claudia Palena, Sofia R. Gameiro, Andrew Nguyen, Kristin C. Hicks, Stephen C. Benz, and Karin L. Lee more...
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Supplementary figures and tables
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- 2023
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73. Supplemental Figures and Table from Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune–Tumor Interactions: Engage, Expand, Enable
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James W. Hodge, Jeffrey Schlom, Houssein Abdul Sater, Rika Fujii, Benjamin Wolfson, Kristen Solocinski, Michelle R. Padget, Anthony S. Malamas, and Kellsye P. Fabian
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Supplemental figures s1-s3 and supplementary table 1
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- 2023
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74. Data from Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune–Tumor Interactions: Engage, Expand, Enable
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James W. Hodge, Jeffrey Schlom, Houssein Abdul Sater, Rika Fujii, Benjamin Wolfson, Kristen Solocinski, Michelle R. Padget, Anthony S. Malamas, and Kellsye P. Fabian
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Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen–targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no antitumor activity, whereas combining two, three, or four agents had minimal antitumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T-cell activity in the periphery and tumor, and antitumor activity associated with decreased regulatory T-cell (Treg) immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. This study provides the rationale for the combination of multimodal immunotherapy agents to engage, enhance, and enable adaptive antitumor immunity. more...
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- 2023
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75. Data from Efficient Tumor Clearance and Diversified Immunity through Neoepitope Vaccines and Combinatorial Immunotherapy
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Duane H. Hamilton, Jeffrey Schlom, Kayvan Niazi, Patrick Soon-Shiong, Shahrooz Rabizadeh, John H. Lee, Lars Rohlin, Peter Ordentlich, Zhen Su, John Z. Sanborn, Claudia Palena, Sofia R. Gameiro, Andrew Nguyen, Kristin C. Hicks, Stephen C. Benz, and Karin L. Lee more...
- Abstract
Progressive tumor growth is associated with deficits in the immunity generated against tumor antigens. Vaccines targeting tumor neoepitopes have the potential to address qualitative defects; however, additional mechanisms of immune failure may underlie tumor progression. In such cases, patients would benefit from additional immune-oncology agents targeting potential mechanisms of immune failure. This study explores the identification of neoepitopes in the MC38 colon carcinoma model by comparison of tumor to normal DNA and tumor RNA sequencing technology, as well as neoepitope delivery by both peptide- and adenovirus-based vaccination strategies. To improve antitumor efficacies, we combined the vaccine with a group of rationally selected immune-oncology agents. We utilized an IL15 superagonist to enhance the development of antigen-specific immunity initiated by the neoepitope vaccine, PD-L1 blockade to reduce tumor immunosuppression, and a tumor-targeted IL12 molecule to facilitate T-cell function within the tumor microenvironment. Analysis of tumor-infiltrating leukocytes demonstrated this multifaceted treatment regimen was required to promote the influx of CD8+ T cells and enhance the expression of transcripts relating to T-cell activation/effector function. Tumor-targeted IL12 resulted in a marked increase in clonality of T-cell repertoire infiltrating the tumor, which when sculpted with the addition of either a peptide or adenoviral neoepitope vaccine promoted efficient tumor clearance. In addition, the neoepitope vaccine induced the spread of immunity to neoepitopes expressed by the tumor but not contained within the vaccine. These results demonstrate the importance of combining neoepitope-targeting vaccines with a multifaceted treatment regimen to generate effective antitumor immunity. more...
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- 2023
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76. Supplementary Figure 1 from Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells
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Jeffrey Schlom, Kwong Yok Tsang, James L. Gulley, Christopher R. Heery, Massimo Fantini, Caroline Jochems, and Benjamin Boyerinas
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Dose response curves for avelumab-mediated ADCC assays of 3 human cancer cell lines using purified NK cells from the same healthy donor as effectors at an effector:target ratio of 25:1.
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- 2023
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77. Supplementary Table 1 from Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer
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Jeffrey Schlom, Christopher R. Heery, Seth M. Steinberg, David J. Liewehr, James W. Hodge, Jo A. Tucker, Benedetto Farsaci, Jennifer L. Marté, Caroline Jochems, Kwong Y. Tsang, Ravi A. Madan, and James L. Gulley more...
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PDF file - 43K, Antigen cascade.
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- 2023
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78. Data from Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
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John W. Greiner, Jeffrey Schlom, Helen Sabzevari, Robert Tighe, Jonathan K. Fallon, and Amanda J. Vandeveer
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Bacillus Calmette–Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452–62. ©2016 AACR. more...
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- 2023
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79. Data from Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury
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James L. Gulley, Jeffrey Schlom, Ravi A. Madan, Philip M. Arlen, William Dahut, Timothy C. Rodell, Italia Grenga, Renee N. Donahue, Jennifer L. Marté, Myrna Rauckhorst, B. Harpreet Singh, and Christopher R. Heery more...
- Abstract
The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinomas as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A phase I dose-escalation (3+3 design) trial enrolled 34 patients at 4 dose levels [3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)]. Expansion cohorts were enrolled at 40- and 80-YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events was observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density, and decreased serum CEA. This is the first-in-human study to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides the rationale for exploration in phase II studies. A randomized phase II chordoma study is now enrolling patients. Cancer Immunol Res; 3(11); 1248–56. ©2015 AACR. more...
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- 2023
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80. Supplementary Materials and Methods from Analyses of Pretherapy Peripheral Immunoscore and Response to Vaccine Therapy
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Jeffrey Schlom, James L. Gulley, Christopher R. Heery, Ravi A. Madan, Nuhad K. Ibrahim, Janet C. Siebert, Brendan Dempsey, Peter S. Kim, Lauren M. Lepone, Italia Grenga, Renee N. Donahue, and Benedetto Farsaci more...
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Custom software for the calculation of the peripheral immunoscore.
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- 2023
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81. Supplementary Figures 1 through 3 and Supplementary Tables 1 through 3 from Analyses of Pretherapy Peripheral Immunoscore and Response to Vaccine Therapy
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Jeffrey Schlom, James L. Gulley, Christopher R. Heery, Ravi A. Madan, Nuhad K. Ibrahim, Janet C. Siebert, Brendan Dempsey, Peter S. Kim, Lauren M. Lepone, Italia Grenga, Renee N. Donahue, and Benedetto Farsaci more...
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Supplementary Figure S1: Gating strategy to identify classic peripheral immune cell types and refined immune cell subsets with phenotypes reflecting immune function that were used to generate the peripheral immunoscores of patients treated with docetaxel plus or minus PANVAC. Supplementary Figure S2: Gating strategy to identify classic peripheral immune cell types and refined immune cell subsets with phenotypes reflecting immune function that were used to generate the peripheral immunoscores of patients treated with Quadramet plus or minus PROSTVAC. Supplementary Figure S3: Point assignment method used in generating peripheral immunoscores. Supplementary Table S1: Antibodies and panels used in flow cytometry analysis to identify immune cells. Supplementary Table S2: PBMC frequencies (min, median, max) and bin cutoffs used in generating peripheral immunoscores in breast cancer patients treated with docetaxel +/- PANVAC vaccine and prostate cancer patients treated with Sm-153 (Quadramet) +/- PROSTVAC vaccine. Supplementary Table S3: Summation of points assigned to individual subsets to generate peripheral immunoscore. more...
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- 2023
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82. Supplemental Figure 1 from Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury
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James L. Gulley, Jeffrey Schlom, Ravi A. Madan, Philip M. Arlen, William Dahut, Timothy C. Rodell, Italia Grenga, Renee N. Donahue, Jennifer L. Marté, Myrna Rauckhorst, B. Harpreet Singh, and Christopher R. Heery more...
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Yeast-brachyury progression-free survival; chordoma patients only.
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- 2023
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83. Data from Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells
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Jeffrey Schlom, Kwong Yok Tsang, James L. Gulley, Christopher R. Heery, Massimo Fantini, Caroline Jochems, and Benjamin Boyerinas
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Several anti–PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti–PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti–PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti–PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. Cancer Immunol Res; 3(10); 1148–57. ©2015 AACR. more...
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- 2023
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84. Supplementary Figure 1 from Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer
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Jeffrey Schlom, Christopher R. Heery, Seth M. Steinberg, David J. Liewehr, James W. Hodge, Jo A. Tucker, Benedetto Farsaci, Jennifer L. Marté, Caroline Jochems, Kwong Y. Tsang, Ravi A. Madan, and James L. Gulley more...
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PDF file - 90K, Consort diagram.
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- 2023
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85. Supplementary Figure 3 from Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer
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Jeffrey Schlom, Christopher R. Heery, Seth M. Steinberg, David J. Liewehr, James W. Hodge, Jo A. Tucker, Benedetto Farsaci, Jennifer L. Marté, Caroline Jochems, Kwong Y. Tsang, Ravi A. Madan, and James L. Gulley more...
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PDF file - 264K, Tumor growth rates following vaccine.
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- 2023
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86. Supplementary Figure 3 from Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
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John W. Greiner, Jeffrey Schlom, Helen Sabzevari, Robert Tighe, Jonathan K. Fallon, and Amanda J. Vandeveer
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PD-L1 expression levels on mouse bladders containing MB49 tumors and on normal mouse bladders.
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- 2023
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87. Supplementary Table 2 from Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer
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Jeffrey Schlom, Christopher R. Heery, Seth M. Steinberg, David J. Liewehr, James W. Hodge, Jo A. Tucker, Benedetto Farsaci, Jennifer L. Marté, Caroline Jochems, Kwong Y. Tsang, Ravi A. Madan, and James L. Gulley more...
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XLSX file - 32K, Adverse events.
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88. Supplementary Tables 1 - 2 from Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells
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Jeffrey Schlom, Kwong Yok Tsang, James L. Gulley, Christopher R. Heery, Massimo Fantini, Caroline Jochems, and Benjamin Boyerinas
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Supplementary Table S1. Pre-treating PBMC with IL-2 did not affect ADCC induced by avelumab of the human lung carcinoma cell line H441. Supplementary Table S2. Pre-treating purified NK cells with IL-12 did not increase ADCC activity mediated by avelumab of the human carcinoma cell lines HT29 and ASPC-1 more than the isotype control. more...
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- 2023
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89. Supplementary Figure 1 from Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
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John W. Greiner, Jeffrey Schlom, Helen Sabzevari, Robert Tighe, Jonathan K. Fallon, and Amanda J. Vandeveer
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Flow cytometric analyses depicting the percentage of splenocytes from mice that express CD4 or CD8 indicating the two T cell subsets.
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- 2023
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90. Data from Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer
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Jeffrey Schlom, Christopher R. Heery, Seth M. Steinberg, David J. Liewehr, James W. Hodge, Jo A. Tucker, Benedetto Farsaci, Jennifer L. Marté, Caroline Jochems, Kwong Y. Tsang, Ravi A. Madan, and James L. Gulley more...
- Abstract
PSA-TRICOM (PROSTVAC) is a novel vector-based vaccine designed to generate a robust immune response against prostate-specific antigen (PSA)-expressing tumor cells. The purpose of this report is to present an overview of both published studies and new data in the evaluation of immune responses to the PSA-TRICOM vaccine platform, currently in phase III testing. Of 104 patients tested for T-cell responses, 57% (59/104) demonstrated a ≥2-fold increase in PSA-specific T cells 4 weeks after vaccine (median 5-fold increase) compared with pre-vaccine, and 68% (19/28) of patients tested mounted post-vaccine immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). The PSA-specific immune responses observed 28 days after vaccine (i.e., likely memory cells) are quantitatively similar to the levels of circulating T cells specific for influenza seen in the same patients. Measurements of systemic immune response to PSA may underestimate the true therapeutic immune response (as this does not account for cells that have trafficked to the tumor) and does not include antigen spreading. Furthermore, although the entire PSA gene is the vaccine, only one epitope of PSA is evaluated in the T-cell responses. Because this therapeutic vaccine is directed at generating a cellular/Th1 immune response (T-cell costimulatory molecules and use of a viral vector), it is not surprising that less than 0.6% of patients (2/349) tested have evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. An ongoing phase III study will evaluate the systemic immune responses and correlation with clinical outcomes. Cancer Immunol Res; 2(2); 133–41. ©2013 AACR. more...
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- 2023
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91. Supplementary Figure 2 from Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
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John W. Greiner, Jeffrey Schlom, Helen Sabzevari, Robert Tighe, Jonathan K. Fallon, and Amanda J. Vandeveer
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Biological and immunologic characteristics of anti-PD-L1.
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- 2023
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92. Supplementary Figure 4 from Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
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John W. Greiner, Jeffrey Schlom, Helen Sabzevari, Robert Tighe, Jonathan K. Fallon, and Amanda J. Vandeveer
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Immunohistochemical detection of CD4 and CD8 immune cell subsets in the bladders of mice treated with Avelumab, BCG or Avelumab plus BCG
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- 2023
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93. Supplementary Figure 2 from Immune Impact Induced by PROSTVAC (PSA-TRICOM), a Therapeutic Vaccine for Prostate Cancer
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Jeffrey Schlom, Christopher R. Heery, Seth M. Steinberg, David J. Liewehr, James W. Hodge, Jo A. Tucker, Benedetto Farsaci, Jennifer L. Marté, Caroline Jochems, Kwong Y. Tsang, Ravi A. Madan, and James L. Gulley more...
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PDF file - 62K, IL-5 following vaccine.
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- 2023
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94. Data from Analyses of Pretherapy Peripheral Immunoscore and Response to Vaccine Therapy
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Jeffrey Schlom, James L. Gulley, Christopher R. Heery, Ravi A. Madan, Nuhad K. Ibrahim, Janet C. Siebert, Brendan Dempsey, Peter S. Kim, Lauren M. Lepone, Italia Grenga, Renee N. Donahue, and Benedetto Farsaci more...
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Tumor immunoscore analyses, especially for primary colorectal cancer and melanoma lesions, provide valuable prognostic information. Metastatic lesions of many carcinoma types, however, are often not easily accessible. We hypothesized that immune cells in peripheral blood may differ among individual patients with metastatic disease, which, in turn, may influence their response to immunotherapy. We thus analyzed immune cell subsets within peripheral blood mononuclear cells to determine if a "peripheral immunoscore" could have any prognostic significance for patients before receiving immunotherapy. Patients with metastatic breast cancer were randomly assigned to receive docetaxel ± PANVAC vaccine. In another trial, prostate cancer patients with metastatic bone lesions were randomly assigned to receive a bone-seeking radionuclide ± PROSTVAC vaccine. Predefined analyses of "classic" immune cell types (CD4, CD8, natural killer cells, regulatory T cells, myeloid-derived suppressor cells, and ratios) revealed no differences in progression-free survival (PFS) for either arm in both trials. Predefined analyses of refined immune cell subsets for which a biologic function had been previously reported also showed no significant prognostic value in PFS for patients receiving either docetaxel or radionuclide alone; however, in patients receiving these agents in combination with vaccine, the peripheral immunoscore of refined subsets revealed statistically significant differences in PFS (P < 0.001) for breast cancer patients receiving docetaxel plus vaccine, and in prostate cancer patients receiving radionuclide plus vaccine (P = 0.004). Larger randomized studies will be required to validate these findings. These studies, however, provide the rationale for the evaluation of refined immune cell subsets to help determine which patients may benefit most from immunotherapy. Cancer Immunol Res; 4(9); 755–65. ©2016 AACR. more...
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- 2023
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95. A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer
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Jason M Redman, Yo-Ting Tsai, Benjamin A Weinberg, Renee N Donahue, Shruti Gandhy, Margaret E Gatti-Mays, Houssein Abdul Sater, Marijo Bilusic, Lisa M Cordes, Seth M Steinberg, Jennifer L Marte, Caroline Jochems, Sunnie S Kim, John L Marshall, Sheri McMahon, Erica Redmond, Jeffrey Schlom, James L Gulley, and Julius Strauss more...
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inorganic chemicals ,Vaccines ,Cancer Research ,Antibodies, Monoclonal, Humanized ,Bevacizumab ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Gastrointestinal Cancer ,otorhinolaryngologic diseases ,Humans ,sense organs ,Immunotherapy ,Colorectal Neoplasms ,psychological phenomena and processes - Abstract
Background FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. Methods Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. Results Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. Conclusions SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell–mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit. more...
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- 2022
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96. A randomized phase 2 study of bicalutamide with or without metformin for biochemical recurrence in overweight or obese prostate cancer patients (BIMET-1)
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Marijo Bilusic, Nicole J. Toney, Renee N. Donahue, Susan Wroblewski, Matthew Zibelman, Pooja Ghatalia, Eric A. Ross, Fatima Karzai, Ravi A. Madan, William L. Dahut, James L. Gulley, Jeffrey Schlom, Elizabeth R. Plimack, and Daniel M. Geynisman more...
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Cancer Research ,Oncology ,Urology - Published
- 2022
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97. Supplementary Table 2 from Serum Antibodies to Blood Group A Predict Survival on PROSTVAC-VF
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Jeffrey C. Gildersleeve, Jeffrey Schlom, James W. Hodge, Oyindasola Oyelaran, James L. Gulley, and Christopher T. Campbell
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PDF file - 112K, Summary of survival correlations for pre-vaccination antibody levels
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- 2023
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98. Supplementary Figure S7 from Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models
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Clint Allen, Paul E. Clavijo, John A. Zebala, Dean Y. Maeda, Jeffrey Schlom, Claudia Palena, Lucas A. Horn, Jay Friedman, Nicole C. Schmitt, Angel P. Huynh, Wojciech K. Mydlarz, Yvette Robbins, and Sarah Greene more...
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Supplemental Figure S7. SX-682 treatment does not alter PMN-MDSC suppressive capacity
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- 2023
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99. Supplementary Data from Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma
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Jeffrey Schlom, William L. Dahut, Herbert Kotz, Seth M. Steinberg, James W. Hodge, Jack P. Higgins, Mary P. Pazdur, Jacquin L. Jones, Vittore Cereda, Cinzia Remondo, Diane J. Poole, Claudia Palena, Junko Yokokawa, Kwong-Yok Tsang, Philip M. Arlen, and James L. Gulley more...
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Supplementary Data from Pilot Study of Vaccination with Recombinant CEA-MUC-1-TRICOM Poxviral-Based Vaccines in Patients with Metastatic Carcinoma
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- 2023
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100. Data from Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors
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James L. Gulley, Christoph Helwig, Lisa Mahnke, Olaf Christensen, Lisa Cordes, Italia Grenga, Renee N. Donahue, Jennifer L. Marté, Elizabeth Lamping, Zhigang Kang, Liang Cao, Ravi A. Madan, Jeffrey Schlom, Christopher R. Heery, and Julius Strauss more...
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Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ “trap.”Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response.Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid).Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR. more...
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- 2023
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