Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma

• Type of Material: Article
• Authors: Anne M. Noonan, Ohio State University; Matthew R. Farren, Ohio State University; Susan M. Geyer, University of South Florida; Ying Huang, Ohio State University; Sanaa Tahiri, Ohio State University; Daniel Ahn, Ohio State University; Sameh Mikhail, Ohio State University; Kristen K. Ciombor, Ohio State University; Shubham Pant, Oklahoma University Cancer Institute; Santiago Aparo, Albert Einstein College of Medicine; Jennifer Sexton, Ohio State University; John L. Marshall, Georgetown University; Thomas A. Mace, Ohio State University; Christina Wu, Emory University; Bassel El-Rayes, Emory University; Cynthia D. Timmers, Ohio State University; James Zwiebel, National Cancer Institute; Gregory Lesinski, Emory University; Miguel A. Villalona-Calero, Ohio State University; Tanios S. Bekaii-Saab, Ohio State University
• Language: English
• Date: 2016-06-01
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Society of Gene & Cell Therapy
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/mt.2016.66
• Title of Journal or Parent Work: Molecular Therapy
• ISSN: 1525-0016
• Volume: 24
• Issue: 6
• Start Page: 1150
• End Page: 1158
• Grant/Funding Information: This study would not have been possible without the support of the following sources: the US National Cancer Institute's Cancer Therapy Evaluation Program (NCT01280058) and associated Phase 2 N01 program grant (HHSN261201100070C), an NIH postdoctoral training grant (5 T32 CA 90223-12) the William Hall Fund for Liver and Pancreatic Cancer Research, Oncolytics, and the Pelotonia Fellowship Program.
• Keywords: REOVIRUS; GEMCITABINE; IMMUNOSUPPRESSION; Life Sciences & Biomedicine; Research & Experimental Medicine; CARCINOMA; MYELOID CELLS; IMMUNOTHERAPY; CANCER; Genetics & Heredity; Science & Technology; PACLITAXEL; RADIOTHERAPY; ANTICANCER CHEMOTHERAPY; Biotechnology & Applied Microbiology; Medicine, Research & Experimental
• Research Categories: Health Sciences, Oncology

Abstract

Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4) + T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.