TY - JOUR
T1 - Elucidation of pelareorep pharmacodynamics in a phase I trial in patients with KRAS-mutated colorectal cancer
AU - Goel, Sanjay
AU - Ocean, Allyson J.
AU - Parakrama, Ruwan Y.
AU - Ghalib, Mohammad H.
AU - Chaudhary, Imran
AU - Shah, Umang
AU - Viswanathan, Sengottuvel
AU - Kharkwal, Himanshu
AU - Coffey, Matthew
AU - Maitra, Radhashree
N1 - Funding Information:
S. Goel reports receiving a commercial research grant from Oncolytics Inc. A.J. Ocean is a consultant (paid consultant) at Celgene and Tyme Therapeutics, Inc., is an advisory board member at Agios and Array, and has received speakers bureau honoraria from Daiichi Sanyko. M. Coffey is president, CEO (paid consultant) at, has ownership interest (including patents) in, and has provided expert testimony for Oncolytics Biotech Inc. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors deeply appreciate the willingness of the patients to participate in the trial and to their families who supported them all along. This study would not have been possible without such contribution. We further want to extend our sincere thanks to Dr. Lydia Tesfa, ex-Associate Director, Flow Cytometry core facility and Ms. Leslie Gunther-Cummins, Electron Microscope Specialist, Analytical Imaging Facility of Albert Einstein College of Medicine (Bronx, NY) for their constant support and guidance throughout the execution of the project.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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-naïve 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 s-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.
AB - 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-naïve 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 s-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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U2 - 10.1158/1535-7163.MCT-19-1117
DO - 10.1158/1535-7163.MCT-19-1117
M3 - Article
C2 - 32156785
AN - SCOPUS:85084272008
SN - 1535-7163
VL - 19
SP - 1148
EP - 1156
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -
