Abstract 2467: Enhanced CD8+T-cell infiltration, PD-L1 expression, and T-cell repertoire expansion in patients with metastatic uveal melanoma responding to treatment with RP2 alone or in combination with nivolumab
Authors: Bommareddy Praveen K. , Kalbasi Alireza , Harrington Kevin J. , Olsson-Brown Anna , Chan Tze Y. , Nenclares Pablo , Leslie Isla , Middleton Mark R. , Cohan David M. , Xynos Konstantinos , Coffin Robert , Sacco Joseph J. 
Published: March 2024

Abstract
Background: Metastatic uveal melanoma (MUM), typically an immune-excluded tumor, has few effective treatments and shows limited clinical response to immunotherapy. RP2 is an enhanced-potency oncolytic HSV-1 that expresses GM-CSF, an anti-CTLA-4 antibody-like molecule, and the fusogenic gibbon ape leukemia virus membrane R− glycoprotein (GALV-GP-R−). Here, we present the biomarker data of RP2 monotherapy and RP2 + nivolumab (nivo; anti-PD-1) in patients (pts) with MUM from an ongoing clinical trial (NCT04336241).
Methods: Tumor biopsies and peripheral blood mononuclear cells (PBMCs) were collected pre-treatment and at Day 43 (D43). The tumor microenvironment (TME) was analyzed by immunohistochemistry (IHC). Systemic peripheral anti-tumor immunity was assessed by sequencing the CDR3β region of the T-cell receptor (TCR) using immunoSEQ Assay. HLA typing was obtained from patient history when available. Correlations between baseline tumor PD-L1 and CD8 expression, HLA type, prior treatment with ipilimumab (ipi)/nivo, and HLA status—vs clinical response status—were assessed.
Results: As of August 2022, 17 pts with MUM were enrolled (RP2 monotherapy, n = 3; RP2 + nivo, n = 14). The majority of pts had previously received both anti-PD-1 and anti-CTLA-4 therapy (12/17, 70.6%), and 17.6% had received ≥3 prior lines of therapy. ORR for the 17 pts was 29.4% (5/17; all PRs; RP2 monotherapy, 1/3; RP2 + nivo, 4/14). Eight pts (2 PR, 3 SD, and 3 PD) had evaluable baseline and post-treatment biopsies for IHC, and 13 pts (4 PR, 4 SD, and 5 PD) had evaluable baseline and post-treatment PBMCs for TCR sequencing analyses. Of the 10 patients that achieved clinical benefit (PR/SD), IHC analysis of all available (n = 5, 2 PR, 3SD) paired biopsies demonstrated an increase in intra-tumoral PD-L1 expression, and 4 patients (2 PR, 2 SD) exhibited an increase in CD8+ T-cell infiltration into tumors at D43. No increase in either CD8+ T-cell infiltration or PD-L1 expression was observed at D43 in patients with PD. There was no correlation between HLA-A2*02:01 status or prior treatment with ipi/nivo and response. In addition, TCR sequencing revealed expansion of pre-existing TCRs (including a tumor antigen-specific clone targeting MART-1 in a responding patient) and generation of new T- cell clones, following RP2 + nivo.
Conclusions: Preliminary RP2 + nivo data demonstrated meaningful antitumor activity in pts with MUM. Biomarker data indicated a conversion of the TME from an immune-excluded to an immune-infiltrated phenotype in responding patients following treatment with RP2 + nivo. Furthermore, systemic peripheral T-cell clonal expansion was noted. These results support further clinical development of RP2 + nivo in pts with MUM.
Citation Format: Praveen K. Bommareddy, Alireza Kalbasi, Kevin J. Harrington, Anna Olsson-Brown, Tze Y. Chan, Pablo Nenclares, Isla Leslie, Mark R. Middleton, David M. Cohan, Konstantinos Xynos, Robert Coffin, Joseph J. Sacco. Enhanced CD8+T-cell infiltration, PD-L1 expression, and T-cell repertoire expansion in patients with metastatic uveal melanoma responding to treatment with RP2 alone or in combination with nivolumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2467.