Safety and efficacy of murine PVSRIPO plus anti-PD-1 immune checkpoint inhibitor (ICI) in a melanoma tumor model.

Abstract

2560 Background: Most patients with advanced melanoma (mel) fail/acquire resistance to ICI, including anti-(α) PD-1. PVSRIPO is a novel intratumoral immunotherapy derived from the Sabin type 1 attenuated poliovirus (PV) that targets CD155, widely expressed on solid tumors and antigen-presenting cells (APCs) of the tumor microenvironment. Therapy leads to direct tumor cell death and type I/III interferon-dominant innate inflammation, mediating priming and recruitment of tumor antigen-specific T cells. Inflammation-mediated upregulation of the PD-1/L1 IC suggests greater anti-tumor response could be achieved with PVSRIPO + αPD-1. The aim of this preclinical study was to evaluate the efficacy and safety of murine PVSRIPO (mRIPO) + αPD-1 in an aggressive mel tumor model (B16-F10.9-OVA in human-CD155 transgenic mice [C56BI/6]). Methods: Mice were randomized to 4 groups (G) of 12: (G1 [control]: vehicle [v] + IgG; G2: v + αPD-1; G3: mRIPO + IgG; G4: mRIPO + αPD-1). Tumor cells (5 x 105) were implanted into the right (R) and left (L) flanks. When tumor volume (vol) was ̃25 mm3, 15 µL v or 1 x 107 TCID50 mRIPO was injected into R (Day 1) and L (Day 4) tumors; αPD-1 or IgG (250 µg, 100 µL ip) was given on Days 1 and 4 and q 3 days until termination (Day 13). Weight, hematology, chemistry, and inflammatory cytokines were assessed pre/post-tumor implantation. Tumor vol was assessed every other day, with gross/histologic exam at termination. Results: 47 mice without health issues were euthanized as planned; 1 G1 animal required early euthanasia for tumor ulceration. Microscopic findings: increased mononuclear cell tumor infiltrates (G2 and G4); less severe L tumor growth necrosis in G2, G3, and G4 vs G1. There were no specific treatment-related changes in serum cytokines in G4. See the table below for summary of total tumor vol changes vs control; the most significant reduction was observed in G4. No tumor cells were observed via histopathology at Day 13 in R flanks of 1 mouse in G2; 3 in G3; and 8 in G4; and only G3 (n=1) and G4 (n=5) mice had no evidence of L flank tumor cells, with regression evident before L tumor mRIPO injection (ie, abscopal response). Conclusions: mRIPO + αPD-1 had the greatest overall anti-tumor response, and the combination was well tolerated. These results suggest combination therapy is not associated with untoward immune-mediated toxicity and highlight the potential for enhanced efficacy in injected and uninjected tumors. A phase 2 clinical trial of PVSRIPO ± αPD-1 in unresectable αPD-1 refractory mel is enrolling (LUMINOS-102, NCT04577807).[Table: see text]