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

Anne M. Noonan, Matthew R. Farren, Susan M. Geyer, Ying Huang, Sanaa Tahiri, Daniel Ahn, Sameh Mikhail, Kristen K. Ciombor, Shubham Pant, Santiago Aparo, Jennifer Sexton, John L. Marshall, Thomas A. Mace, Christina S. Wu, Bassel El-Rayes, Cynthia D. Timmers, James Zwiebel, Gregory B. Lesinski, Miguel A. Villalona-Calero, Tanios Bekaii-Saab

Research output: Contribution to journalArticle

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1150-1158
Number of pages9
JournalMolecular Therapy
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Noonan, A. M., Farren, M. R., Geyer, S. M., Huang, Y., Tahiri, S., Ahn, D., Mikhail, S., Ciombor, K. K., Pant, S., Aparo, S., Sexton, J., Marshall, J. L., Mace, T. A., Wu, C. S., El-Rayes, B., Timmers, C. D., Zwiebel, J., Lesinski, G. B., Villalona-Calero, M. A., & Bekaii-Saab, T. (2016). Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. Molecular Therapy, 24(6), 1150-1158. https://doi.org/10.1038/mt.2016.66