Elucidation of Pelareorep Pharmacodynamics in A Phase I Trial in Patients with
| Autor: | Sanjay, Goel, Allyson J, Ocean, Ruwan Y, Parakrama, Mohammad H, Ghalib, Imran, Chaudhary, Umang, Shah, Sengottuvel, Viswanathan, Himanshu, Kharkwal, Matthew, Coffey, Radhashree, Maitra |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Maximum Tolerated Dose Mice Nude Apoptosis Irinotecan Prognosis Combined Modality Therapy Xenograft Model Antitumor Assays Article Bevacizumab Proto-Oncogene Proteins p21(ras) Mice Oncolytic Viruses Antineoplastic Combined Chemotherapy Protocols Mutation Biomarkers Tumor Tumor Cells Cultured Animals Humans Female Colorectal Neoplasms Aged Cell Proliferation |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 |
| Popis: | 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/m(2)) and pelareorep (1x10(10) TCID(50)-3x10(10) TCID(50)) 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 (180mg/m(2) irinotecan) and pelareorep (3x10(10) TCID(50)) was well tolerated, without a DLT. At the RPTD, three of six 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. |
| Databáze: | OpenAIRE |
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