Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.

Abstract

4144 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x1010 TCID50 IV on Days 1, 2, 3 & 8 of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.