Anti-PD1 plus oncolytic virus as first-line treatment option for metastatic renal cell carcinomas.

Abstract

675 Background: Although anti-programmed death (PD)1 and anti-cytotoxic T-cell lymphocyte (CTLA)-4 combination therapy is recommended as one of the first line treatment options for metastatic renal cell carcinoma (mRCC), immune checkpoint inhibitor (ICI) combination therapy leads to the increased immune-mediated adverse events (imAEs). Our group has reported the therapeutic potential of oncolytic virus, JX-594 in metastatic murine RCC model. In this study, we explored the effect of JX-594 plus anti-PD1 in comparison to the combination therapy of anti-PD1 and anti-CTLA-4. Methods: Early-stage and advanced-stage highly metastatic orthotopic murine RCC models developed by our group were used. Anti-PD1 with either JX-594 or anti-CTLA-4 were systemically injected through the peritoneum. Immunofluorescence analysis was performed to demonstrate the remodeling of the tumor immune microenvironment (TIME). Results: Both JX-594 plus anti-PD1 and ICI combination therapy significantly reduced primary tumor and metastatic tumor burden in lung and peritoneum compared to cytoreductive nephrectomy plus anti-PD1. For the early-stage and advanced-stage mRCC models, JX-594 plus anti-PD1 significantly decreased the primary tumor sizes and number of lung tumor nodules compared to ICI combination therapy only in the early-stage mRCC model ( P<0.01), but not in advanced-stage mRCC model ( P=0.07). The therapeutic benefit was significantly increased when JX-594 and anti-PD1 was sequentially injected compared to when JX-594 and anti-PD1 was injected simultaneously ( P<0.05). Notable imAEs were observed in 2/16 (12.5%) in ICI combination group, whereas no notable imAEs in JX-594 plus anti-PD1 group. JX-594 plus anti-PD1 induced changes in TIME of both early- and advanced-stage mRCC model. However, tumor-suppressing TIME was more notable in early-stage mRCC model, which increased tumor-infiltrating CD8+ T cells and tumor-suppressing M1 tumor-associated macrophages (TAM), and decreased tumor-promoting myeloid-derived suppressor cells (MDSCs) and M2 TAM. Conclusions: JX-594 plus anti-PD1 effectively reduced primary tumors and metastatic burdens similar to ICI combination therapy. Furthermore, imAEs significantly decreased in JX-594 plus anti-PD1 group, suggesting the potential benefit of JX-594 plus anti-PD1 for reserving ICI induced toxicities, especially by anti-CTLA-4.