Journal
MOLECULAR THERAPY
Volume 24, Issue 6, Pages 1150-1158Publisher
CELL PRESS
DOI: 10.1038/mt.2016.66
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Funding
- US National Cancer Institute's Cancer Therapy Evaluation Program [NCT01280058]
- Phase 2 N01 program [HHSN261201100070C]
- NIH [5 T32 CA 90223-12, 1 T32 CA 165998-01]
- William Hall Fund for Liver and Pancreatic Cancer Research, Oncolytics
- Pelotonia Fellowship Program
- Pelotonia Research Foundation
- Pfizer
- Boston Biomedical
- MedImmune
- Onyx Pharmaceuticals
- Bayer
- Boehringer Ingelheim
- Bristol-Myers Squibb
- Albert Einstein College of Medicine
- NIH/NCI
- Georgetown University
- Merrimack
- Genentech
- Oncolytics
- NCI
- Karyopharm
- Chirhoclin
- American College for Gastroenterology
- Merck
- Hoosier Cancer Research Network
- US National Cancer Institute
- National Comprehensive Cancer Network
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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.
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