The Experts below are selected from a list of 144 Experts worldwide ranked by ideXlab platform
Devalingam Mahalingam - One of the best experts on this subject based on the ideXlab platform.
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Pembrolizumab in combination with the oncolytic virus Pelareorep in patients progressing on systemic chemotherapy for advanced pancreatic adenocarcinoma: A phase II study.
Journal of Clinical Oncology, 2020Co-Authors: Devalingam Mahalingam, Grey A. Wilkinson, Aparna Kalyan, Sheetal Mehta Kircher, Victoria Maurer, Masha Kocherginsky, Pedro Viveiros, Elena Vagia, Matthew C. CoffeyAbstract:e16789Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Analysis of tumor tissue from p...
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Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019Co-Authors: Devalingam Mahalingam, Grey A. Wilkinson, Kevin H. Eng, Paul Fields, Patrick Raber, Gerard J. Nuovo, Matthew C. Coffey, Jennifer L. Moseley, Karol Cheetham, Pawel KalinskiAbstract:Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell–inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with Pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that Pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective. Methods: A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received Pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies. Results: Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit. Conclusions: Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of Pelareorep and anti–PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for Pelareorep therapy warranting further investigation.
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Abstract 2272: Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus Pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: Grey A. Wilkinson, Paul Fields, Sukeshi Patel Arora, Patrick Raber, Devalingam Mahalingam, Karol Cheetham, Matthew C. CoffeyAbstract:Background: Pelareorep is an immuno-oncolytic virus that induces an inflamed tumor phenotype in metastatic adenocarcinoma of the pancreas (MAP). Systemically delivered Pelareorep in combination with chemotherapy achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Analysis of tumor tissue from patients (pts) treated with Pelareorep, chemotherapy and anti-PD-L1 have shown reovirus RNA and protein replication, T-cell infiltration, and upregulation of PD-L1, highlighting that effective T-cell recognition of tumor antigens may be critical to success for this combination therapy. Thus, we hypothesized that Pelareorep in combination with chemo and pembrolizumab in pts with MAP would alter the peripheral T-cell repertoire, creating new T-cell clones via the release of novel neoantigens in addition to expanding existing T-cell clones. Methods: A phase 1b study enrolled 11 MAP pts who progressed after first-line treatment. Pts received Pelareorep (4.5e10 TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1) 5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. DNA from peripheral blood mononuclear cells from nine patients at cycle 1 day 1 (C1D1) & C2D1 (approx. 3 weeks later) was analyzed using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle) sequencing the T-cell receptor beta chain region to interrogate changes in the T-cell repertoire. Results: The median Morisita index between C2D1 and C1D1 was 0.83 with 3 samples below 0.6, indicative of significant peripheral repertoire turnover. The median number of expanded clones equated to 45.7 per 100,000 cumulative templates; normal variation over 4 weeks is ~ 5-10 expanded clones. Strikingly, most (median: 86%) peripheral clonal expansion occurred in clones below the limit of detection at C1D1. Cox regression analysis revealed that high peripheral clonality correlates with progression free survival at C1D1 (p=0.01, HR=0.053). Moreover, high clonality correlates with overall survival at both C1D1 (p=0.013, HR=0.124) and C2D1 (p=0.010, HR=0.079). Conclusions: High levels of peripheral T-cell repertoire turnover occur between C1D1 and C2D1. Repertoire turnover is accompanied by significant clonal expansion, mostly by expansion of new clones (i.e. undetected in C1D1). Higher peripheral clonality is associated with better progression free survival at C1D1, and overall survival at C1D1 and C2D1. This research highlights the potential utility of T-cell clonality as a predictive and prognostic biomarker to Pelareorep therapy and warrants further clinical investigation. Citation Format: Grey A. Wilkinson, Devalingam Mahalingam, Sukeshi Patel Arora, Paul A. Fields, Patrick Raber, Karol Cheetham, Matt Coffey. Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus Pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2272.
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Prediction of response to Pelareorep plus pembrolizumab in pancreatic ductal adenocarcinoma (PDAC).
Journal of Clinical Oncology, 2019Co-Authors: Christos Fountzilas, Grey A. Wilkinson, Kevin H. Eng, Paul Fields, Sukeshi Patel Arora, Pawel Kalinski, Patrick Raber, Gerard J. Nuovo, Matthew C. Coffey, Devalingam MahalingamAbstract:e15726Background: Pelareorep is an oncolytic reovirus that can induce an inflamed T-cell-infiltrated (hot) phenotype in PDAC. In a phase Ib trial, Pelareorep was administered in combination with pe...
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
Cancers, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew C. CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naive patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC.
Romit Chakrabarty - One of the best experts on this subject based on the ideXlab platform.
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
Cancers, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew C. CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naive patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC.
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Pelareorep to promote the expression of a IFN-gamma-related gene signature that predicts response to checkpoint blockade therapy.
Journal of Clinical Oncology, 2018Co-Authors: Grey A. Wilkinson, Hue Tran, Romit Chakrabarty, Aine Piar, Christopher Resnyk, M. Jordan Humphrey, Keith Glendinning, Andres A. Gutierrez, Matthew C. CoffeyAbstract:3089Background: A clinical study in patients (pts) with metastatic breast cancer (mBC) treated with Pelareorep resulted in significant improvements in overall survival. Clinical studies with checkp...
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
MDPI AG, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC
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A phase II study of REOLYSIN^® (Pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Devalingam Mahalingam, Christos Fountzilas, Nicole Noronha, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew Coffey, Brad Thompson, Jennifer Moseley, John SarantopoulosAbstract:REOLYSIN^® (Pelareorep) is an investigational new drug, consisting of a live, replication-competent, Reovirus Type 3 Dearing strain in a proprietary formulation. Several preclinical and clinical trials with REOLYSIN^® on a wide range of cancer indications have demonstrated antineoplastic activity on cells with activated RAS-signaling pathway. Furthermore, long-term survival benefits were evident in post-treatment patients indicating a potential antitumor immune response triggered by REOLYSIN^®. Numerous mono and/or combination therapy studies with the agent showed a consistent safety profile. The current study is a phase II, single-arm, open label trial of REOLYSIN^® in combination with carboplatin and paclitaxel for patients with advanced melanoma. Results from the 14 patients enrolled in the study exhibited no grade 4 adverse events or deaths but manageable grade-3 toxicities commonly attributed to REOLYSIN^®, including pyrexia, chills, myalgia, pain, fatigue, and nausea. The number of treatment cycles ranged from 2 to 20 with a median of 6 cycles. The study met its treatment and efficacy goal for the first stage with three partial responses (ORR was 21%). No complete responses were noted. The median PFS and OS were 5.2 and 10.9 months, respectively. The 1-year OS was 43% with a disease control rate of 85%. In conclusion, REOLYSIN^® combined with carboplatin and paclitaxel is a safe and potentially efficacious therapy for patients with advanced malignant melanoma. Additional combination studies using REOLYSIN^® with chemo/immunotherapy drugs may support more favorable outcomes for patients in this indication.
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The oncolytic virus, Pelareorep, as a novel anticancer agent: a review
Investigational New Drugs, 2015Co-Authors: Romit Chakrabarty, Hue Tran, Giovanni Selvaggi, Allison Hagerman, Brad Thompson, Matt CoffeyAbstract:Pelareorep (REOLYSIN®) is an investigational new drug, a proprietary formulation consisting of a live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. Through several preclinical studies it was determined that reovirus can exhibit profound cytotoxic effects on cancer cells predominantly with an activated RAS-signalling pathway. Moreover, it was discovered that reoviruses can “hitchhike” on peripheral blood mononuclear cells and dendritic cells, thereby evading neutralizing antibodies of the host immune system. Cell carriage, targeted delivery, triggering host immune response and other inherent characteristics of the reovirus led to its further advancement into cancer therapy. When injected into Sprague–Dawley rats, the viral routes of clearance, predominantly through the spleen and liver, remained consistent with earlier studies. Toxicology findings were considered incidental and not associated with Pelareorep when tested in animal models. Pelareorep demonstrated a high level of homogeneity at the amino acid level and genetic stability when compared to the master and working virus banks. The drug is manufactured in a 100 L bioreactor after which it is purified and formulated for use in pre-clinical, clinical and research studies. Over the past few decades, we have witnessed a paradigm shift from conventional therapy to the conceivable use of oncolytic viruses for the treatment of cancer. This review will detail pre-clinical evidence of anticancer activity of Pelareorep that has led to extensive clinical development. Several Phase I-II clinical trials have been completed or are ongoing in cancer patients on a broad spectrum of solid tumors and hematologic malignancies.
Hue Tran - One of the best experts on this subject based on the ideXlab platform.
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
Cancers, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew C. CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naive patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC.
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Pelareorep to promote the expression of a IFN-gamma-related gene signature that predicts response to checkpoint blockade therapy.
Journal of Clinical Oncology, 2018Co-Authors: Grey A. Wilkinson, Hue Tran, Romit Chakrabarty, Aine Piar, Christopher Resnyk, M. Jordan Humphrey, Keith Glendinning, Andres A. Gutierrez, Matthew C. CoffeyAbstract:3089Background: A clinical study in patients (pts) with metastatic breast cancer (mBC) treated with Pelareorep resulted in significant improvements in overall survival. Clinical studies with checkp...
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
MDPI AG, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC
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A phase II study of REOLYSIN^® (Pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Devalingam Mahalingam, Christos Fountzilas, Nicole Noronha, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew Coffey, Brad Thompson, Jennifer Moseley, John SarantopoulosAbstract:REOLYSIN^® (Pelareorep) is an investigational new drug, consisting of a live, replication-competent, Reovirus Type 3 Dearing strain in a proprietary formulation. Several preclinical and clinical trials with REOLYSIN^® on a wide range of cancer indications have demonstrated antineoplastic activity on cells with activated RAS-signaling pathway. Furthermore, long-term survival benefits were evident in post-treatment patients indicating a potential antitumor immune response triggered by REOLYSIN^®. Numerous mono and/or combination therapy studies with the agent showed a consistent safety profile. The current study is a phase II, single-arm, open label trial of REOLYSIN^® in combination with carboplatin and paclitaxel for patients with advanced melanoma. Results from the 14 patients enrolled in the study exhibited no grade 4 adverse events or deaths but manageable grade-3 toxicities commonly attributed to REOLYSIN^®, including pyrexia, chills, myalgia, pain, fatigue, and nausea. The number of treatment cycles ranged from 2 to 20 with a median of 6 cycles. The study met its treatment and efficacy goal for the first stage with three partial responses (ORR was 21%). No complete responses were noted. The median PFS and OS were 5.2 and 10.9 months, respectively. The 1-year OS was 43% with a disease control rate of 85%. In conclusion, REOLYSIN^® combined with carboplatin and paclitaxel is a safe and potentially efficacious therapy for patients with advanced malignant melanoma. Additional combination studies using REOLYSIN^® with chemo/immunotherapy drugs may support more favorable outcomes for patients in this indication.
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The oncolytic virus, Pelareorep, as a novel anticancer agent: a review
Investigational New Drugs, 2015Co-Authors: Romit Chakrabarty, Hue Tran, Giovanni Selvaggi, Allison Hagerman, Brad Thompson, Matt CoffeyAbstract:Pelareorep (REOLYSIN®) is an investigational new drug, a proprietary formulation consisting of a live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. Through several preclinical studies it was determined that reovirus can exhibit profound cytotoxic effects on cancer cells predominantly with an activated RAS-signalling pathway. Moreover, it was discovered that reoviruses can “hitchhike” on peripheral blood mononuclear cells and dendritic cells, thereby evading neutralizing antibodies of the host immune system. Cell carriage, targeted delivery, triggering host immune response and other inherent characteristics of the reovirus led to its further advancement into cancer therapy. When injected into Sprague–Dawley rats, the viral routes of clearance, predominantly through the spleen and liver, remained consistent with earlier studies. Toxicology findings were considered incidental and not associated with Pelareorep when tested in animal models. Pelareorep demonstrated a high level of homogeneity at the amino acid level and genetic stability when compared to the master and working virus banks. The drug is manufactured in a 100 L bioreactor after which it is purified and formulated for use in pre-clinical, clinical and research studies. Over the past few decades, we have witnessed a paradigm shift from conventional therapy to the conceivable use of oncolytic viruses for the treatment of cancer. This review will detail pre-clinical evidence of anticancer activity of Pelareorep that has led to extensive clinical development. Several Phase I-II clinical trials have been completed or are ongoing in cancer patients on a broad spectrum of solid tumors and hematologic malignancies.
Sukeshi Patel Arora - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2272: Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus Pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: Grey A. Wilkinson, Paul Fields, Sukeshi Patel Arora, Patrick Raber, Devalingam Mahalingam, Karol Cheetham, Matthew C. CoffeyAbstract:Background: Pelareorep is an immuno-oncolytic virus that induces an inflamed tumor phenotype in metastatic adenocarcinoma of the pancreas (MAP). Systemically delivered Pelareorep in combination with chemotherapy achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Analysis of tumor tissue from patients (pts) treated with Pelareorep, chemotherapy and anti-PD-L1 have shown reovirus RNA and protein replication, T-cell infiltration, and upregulation of PD-L1, highlighting that effective T-cell recognition of tumor antigens may be critical to success for this combination therapy. Thus, we hypothesized that Pelareorep in combination with chemo and pembrolizumab in pts with MAP would alter the peripheral T-cell repertoire, creating new T-cell clones via the release of novel neoantigens in addition to expanding existing T-cell clones. Methods: A phase 1b study enrolled 11 MAP pts who progressed after first-line treatment. Pts received Pelareorep (4.5e10 TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1) 5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. DNA from peripheral blood mononuclear cells from nine patients at cycle 1 day 1 (C1D1) & C2D1 (approx. 3 weeks later) was analyzed using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle) sequencing the T-cell receptor beta chain region to interrogate changes in the T-cell repertoire. Results: The median Morisita index between C2D1 and C1D1 was 0.83 with 3 samples below 0.6, indicative of significant peripheral repertoire turnover. The median number of expanded clones equated to 45.7 per 100,000 cumulative templates; normal variation over 4 weeks is ~ 5-10 expanded clones. Strikingly, most (median: 86%) peripheral clonal expansion occurred in clones below the limit of detection at C1D1. Cox regression analysis revealed that high peripheral clonality correlates with progression free survival at C1D1 (p=0.01, HR=0.053). Moreover, high clonality correlates with overall survival at both C1D1 (p=0.013, HR=0.124) and C2D1 (p=0.010, HR=0.079). Conclusions: High levels of peripheral T-cell repertoire turnover occur between C1D1 and C2D1. Repertoire turnover is accompanied by significant clonal expansion, mostly by expansion of new clones (i.e. undetected in C1D1). Higher peripheral clonality is associated with better progression free survival at C1D1, and overall survival at C1D1 and C2D1. This research highlights the potential utility of T-cell clonality as a predictive and prognostic biomarker to Pelareorep therapy and warrants further clinical investigation. Citation Format: Grey A. Wilkinson, Devalingam Mahalingam, Sukeshi Patel Arora, Paul A. Fields, Patrick Raber, Karol Cheetham, Matt Coffey. Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus Pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2272.
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Prediction of response to Pelareorep plus pembrolizumab in pancreatic ductal adenocarcinoma (PDAC).
Journal of Clinical Oncology, 2019Co-Authors: Christos Fountzilas, Grey A. Wilkinson, Kevin H. Eng, Paul Fields, Sukeshi Patel Arora, Pawel Kalinski, Patrick Raber, Gerard J. Nuovo, Matthew C. Coffey, Devalingam MahalingamAbstract:e15726Background: Pelareorep is an oncolytic reovirus that can induce an inflamed T-cell-infiltrated (hot) phenotype in PDAC. In a phase Ib trial, Pelareorep was administered in combination with pe...
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
Cancers, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew C. CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naive patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC.
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A study of Pelareorep in combination with pembrolizumab and chemotherapy in patients (pts) with relapsed metastatic adenocarcinoma of the pancreas (MAP).
Journal of Clinical Oncology, 2018Co-Authors: Devalingam Mahalingam, Christos Fountzilas, Jennifer L. Moseley, Karol Cheetham, Nicole Noronha, Adrian Dzugalo, Gerard Nuovo, Andres Gutierrez, Sukeshi Patel AroraAbstract:283 Background: Pelareorep (REOLYSIN) is a immuno-oncolytic virus (IOV) that induces an inflamed tumor phenotype secondary to viral infection of cancer cells. In combination with chemotherapy, it achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Tumor analysis from pts showed reovirus protein replication, T-cell infiltration and upregulation of PD-L1. Similarly, the combination of Pelareorep with anti-PD-1 antibody documented survival benefit in a pre-clinical model. We hypothesized that Pelareorep in combination with chemo and pembrolizumab in pts with MAP would be clinically efficacious. Methods: A phase 1b study enrolled MAP pts who progressed after first line treatment. Pts received Pelareorep (4.5 x 10 10TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1)5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. The primary endpoint was safety. Secondary objectives included tumor response & evaluation for reovirus replication/immune analysis. Results: 11 pts were enrolled with Pelareorep, pembrolizumab and gem (n = 6), 5-FU (n = 3), or iri (n = 2). Most common grade 1 or 2 TEAEs include: fever (73%), headache (55%), chills (46%), dehydration (36%), fatigue (27%) and anemia (27%). One pt (gem arm), transient Gr 2 increased transaminases was reported on two occasions. Grade 3 or 4 TEAEs occurred in 8 pts (73%): abdominal pain, anemia, arthralgias, biliary obstruction, chills, DVT, diarrhea, fever, hyperglycemia, leukopenia, myalgias, nausea, neutropenia, pulmonary emboli, urinary tract infection and vomiting. Of the 5 efficacy evaluable pts, one had PR (13.8 m duration) and 2 SD (lasting 126 and 277 days). Eight died secondary to PD. On-treatment biopsy show reovirus infection in cancer cells and immune infiltrates. Conclusions: The combination therapy showed manageable safety profiles and antitumor activity in previously treated MAP pts. Further evaluation of anti-tumor activity of Pelareorep and anti-PD-1 antibody ± chemotherapy combos is planned. Clinical trial information: NCT02620423.
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A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma
MDPI AG, 2018Co-Authors: Devalingam Mahalingam, Sukeshi Patel Arora, Sanjay Goel, Santiago Aparo, Nicole Noronha, Andres Gutierrez, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Matthew CoffeyAbstract:Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, Pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that Pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that Pelareorep complements single agent gemcitabine in PDAC
Matthew C. Coffey - One of the best experts on this subject based on the ideXlab platform.
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Pembrolizumab in combination with the oncolytic virus Pelareorep in patients progressing on systemic chemotherapy for advanced pancreatic adenocarcinoma: A phase II study.
Journal of Clinical Oncology, 2020Co-Authors: Devalingam Mahalingam, Grey A. Wilkinson, Aparna Kalyan, Sheetal Mehta Kircher, Victoria Maurer, Masha Kocherginsky, Pedro Viveiros, Elena Vagia, Matthew C. CoffeyAbstract:e16789Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Analysis of tumor tissue from p...
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Elucidation of Pelareorep Pharmacodynamics in A Phase I Trial in Patients with KRAS-Mutated Colorectal Cancer
Molecular cancer therapeutics, 2020Co-Authors: Sanjay Goel, Matthew C. Coffey, Allyson J. Ocean, Ruwan Parakrama, M. H. Ghalib, Imran Chaudhary, Umang Shah, Sengottuvel Viswanathan, Himanshu Kharkwal, Radhashree MaitraAbstract:KRAS mutation is a negative predictive biomarker of anti-EGFR agents in patients with metastatic colorectal cancer (mCRC), and remains an elusive target. Pelareorep, a double-stranded RNA virus selectively replicates in KRAS-mutated cells, and is synergistic with irinotecan. A dose escalation trial of FOLFIRI/bevacizumab [irinotecan (150-180 mg/m2) and Pelareorep (1 × 1010 TCID50-3 × 1010 TCID50)] was implemented in adult patients with oxaliplatin refractory/intolerant, KRAS-mutant mCRC. Pelareorep was administered intravenously over 1 hour on days 1-5 every 4 weeks. Additional studies included pharmacokinetics, tumor morphology, and immune responses. Among FOLFIRI-naive patients, the highest dose of FOLFIRI/bevacizumab (180 mg/m2 irinotecan) and Pelareorep (3 × 1010 TCID50) was well tolerated, without a dose-limiting toxicity. At the recommended phase II dose, 3 of 6 patients (50%) had a partial response; the median progression-free and overall survival (PFS, OS) were 65.6 weeks and 25.1 months, respectively. Toxicities included myelosuppression, fatigue, and diarrhea. Transmission electron microscopy revealed viral factories (viral collections forming vesicular structures), at various stages of development. Immunogold staining against viral capsid σ-1 protein demonstrated viral "homing" in the tumor cells. The nucleus displayed sufficient euchromatin regions suggestive of active transcription. Flow cytometry revealed rapid dendritic cell maturation (48 hours) with subsequent activation of cytotoxic T cells (7 days). The combination of Pelareorep with FOLFIRI/bevacizumab is safe. The PFS and OS data are encouraging and deserve further exploration. Pelareorep leads to a clear recurrent immune stimulatory response with cytotoxic T-cell activation, and homes and replicates in the tumor.
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Proteasome Inhibitors Impair the Innate Antiviral Immune Response and Potentiate Pelareorep-Based Viral Therapy in Multiple Myeloma
Blood, 2019Co-Authors: Ada Dona, Matthew C. Coffey, Domenico Viola, Enrico Caserta, Francesca Besi, James F. Sanchez, Guido Marcucci, Jonathan J Keats, Amrita Krishnan, Douglas W. SborovAbstract:INTRODUCTION: Pelareorep is the infusible form of human reovirus (RV). Our single-agent phase 1 RV trial in relapsed multiple myeloma (MM) showed that Pelareorep treatment selectively infected MM cells, as viral RNA was found in myeloma cells and not the bone marrow (BM) stroma. However, we did not observe apoptosis. Our ongoing phase 1 trial, which combines the proteasome inhibitor carfilzomib with RV, has demonstrated RV infection, apoptosis, and clinical responses. We investigated the molecular mechanisms behind the role of a PI (carfilzomib) in this setting. RESULTS: In all MM cell lines we tested (n=4), independently from their sensitivity to RV infection (Stiff et al., Mol Cancer Ther, 2016), viral replication and apoptosis was impaired when MM cells were directly exposed to PIs (carfilzomib and bortezomib). When this experiment was repeated in the setting of the bone marrow cellular fraction or peripheral blood mononuclear cells (PBMCs), it had the opposite effect, as the addition of PI to RV increased RV replication and apoptosis in MM cells. When we washed PBMCs after overnight exposure to RV+PI or to either single agent, then added MM cells, we observed higher infection and apoptosis in cancer cells co-cultured with RV+PI compared to levels from PBMCs treated with each of the single agents, suggesting that PIs increase the ability of PBMCs to serve as a reservoir for infectious reovirus. Monocytes (CD14+) can engage in phagocytosis of reovirus (Berkeley et al., Cancer Immunol Res, 2018), and accordingly we found that RV genome and capsid protein production were detected in CD14+ cells, but not in CD14-depleted PBMCs, and increased upon PI treatment compared to that in RV-treated CD14+ cells. Given that the NF-κB complex is a key proinflammatory signaling pathway associated with the early innate-antiviral immune response, and because PIs can block the degradation of the NF-κB inhibitor IκBα upon phosphorylation, we investigated the effect of the specific IκBα inhibitor Bay-11 in RV viral replication. Our data show that either PI or Bay-11 can inhibit RV-induced IκBα phosphorylation and its subsequent degradation upon RV infection in CD14+ cells, an effect associated with higher capsid formation in RV-treated CD14+ cells in combination with PI or Bay-11, compared to levels from RV alone. Cytokine profiling in PBMCs and CD14+ cells treated with RV in combination with either PI or Bay-11 showed a significant decrease in IFN-α and IFN-β (IFNs) levels and a concomitant increase in RV replication, in contrast to levels from RV alone (p<0.001). We then decided to investigate whether CD14 depletion could affect RV delivery to the cancer cells invivo. Upon intra-femoral injection of 5TGM1 MM cells into syngeneic C57BL/KaLwRij mice, the mice in which the monocytes were depleted by clodronate-liposome treatment before intravenous RV injection showed lower capsid protein formation in the BM MM cells compared to that in mice where the monocytic population was intact. Because monocytes respond to infection by dividing into macrophages to eliminate pathogens, we wanted to investigate whether PI could impair this effect. Intriguingly, although higher levels of viral genome were detected in PI+RV-treated CD14+ cells compared to RV-treated cells (p<0.01), PI abolished ex-vivo RV-induced monocyte differentiation (n=3, p<0.001), without affecting the ability of RV-infected CD14+ cells to induce higher MM cell killing as compared to that from the CD14+ fraction treated with either single agent. Immune killing assays showed that RV-infected MM cells are more susceptible than non-infected cells to T cell effectors (p<0.001), a mechanism that is further potentiated by the addition of PI. In fact, in contrast to the PI-induced blocking of monocyte expansion and activation in response to the virus (n=3, p<0.001), our data suggest that the PI potentiate the expansion of CD8+ T cells, both ex vivo and in two RV+PI treated patients we analyzed so far. CONCLUSIONS: Here we report for the first time that PIs enhance Pelareorep entry, infection, and killing of myeloma cells through its effect on the CD14+ fraction. Reovirus infection and replication within CD14+ cells are augmented by PI-induced NF-κB inhibition of the early innate pro-inflammatory immune response. We also report for the first time that carfilzomib induces direct T cell activation and potentiates T cell killing activity against RV-infected MM cells. Disclosures Krishnan: Takeda: Research Funding; Celgene, Z Predicta: Other: Stock Ownership; Amgen, Takeda: Speakers Bureau; Sutro BioPharma, zPredicta: Consultancy; Celgene, Janssen, Sanofi, BMS: Consultancy. Sborov:Celgene: Honoraria; Janssen: Consultancy. Hofmeister:Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees.
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Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019Co-Authors: Devalingam Mahalingam, Grey A. Wilkinson, Kevin H. Eng, Paul Fields, Patrick Raber, Gerard J. Nuovo, Matthew C. Coffey, Jennifer L. Moseley, Karol Cheetham, Pawel KalinskiAbstract:Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell–inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with Pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that Pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective. Methods: A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received Pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies. Results: Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit. Conclusions: Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of Pelareorep and anti–PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for Pelareorep therapy warranting further investigation.
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Abstract 2272: Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus Pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: Grey A. Wilkinson, Paul Fields, Sukeshi Patel Arora, Patrick Raber, Devalingam Mahalingam, Karol Cheetham, Matthew C. CoffeyAbstract:Background: Pelareorep is an immuno-oncolytic virus that induces an inflamed tumor phenotype in metastatic adenocarcinoma of the pancreas (MAP). Systemically delivered Pelareorep in combination with chemotherapy achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Analysis of tumor tissue from patients (pts) treated with Pelareorep, chemotherapy and anti-PD-L1 have shown reovirus RNA and protein replication, T-cell infiltration, and upregulation of PD-L1, highlighting that effective T-cell recognition of tumor antigens may be critical to success for this combination therapy. Thus, we hypothesized that Pelareorep in combination with chemo and pembrolizumab in pts with MAP would alter the peripheral T-cell repertoire, creating new T-cell clones via the release of novel neoantigens in addition to expanding existing T-cell clones. Methods: A phase 1b study enrolled 11 MAP pts who progressed after first-line treatment. Pts received Pelareorep (4.5e10 TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1) 5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. DNA from peripheral blood mononuclear cells from nine patients at cycle 1 day 1 (C1D1) & C2D1 (approx. 3 weeks later) was analyzed using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle) sequencing the T-cell receptor beta chain region to interrogate changes in the T-cell repertoire. Results: The median Morisita index between C2D1 and C1D1 was 0.83 with 3 samples below 0.6, indicative of significant peripheral repertoire turnover. The median number of expanded clones equated to 45.7 per 100,000 cumulative templates; normal variation over 4 weeks is ~ 5-10 expanded clones. Strikingly, most (median: 86%) peripheral clonal expansion occurred in clones below the limit of detection at C1D1. Cox regression analysis revealed that high peripheral clonality correlates with progression free survival at C1D1 (p=0.01, HR=0.053). Moreover, high clonality correlates with overall survival at both C1D1 (p=0.013, HR=0.124) and C2D1 (p=0.010, HR=0.079). Conclusions: High levels of peripheral T-cell repertoire turnover occur between C1D1 and C2D1. Repertoire turnover is accompanied by significant clonal expansion, mostly by expansion of new clones (i.e. undetected in C1D1). Higher peripheral clonality is associated with better progression free survival at C1D1, and overall survival at C1D1 and C2D1. This research highlights the potential utility of T-cell clonality as a predictive and prognostic biomarker to Pelareorep therapy and warrants further clinical investigation. Citation Format: Grey A. Wilkinson, Devalingam Mahalingam, Sukeshi Patel Arora, Paul A. Fields, Patrick Raber, Karol Cheetham, Matt Coffey. Exploratory analysis of T cell repertoire dynamics upon systemic treatment with the oncolytic virus Pelareorep in combination with pembrolizumab and chemotherapy in patients with advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2272.