Combination of oncolytic Maraba virus with immune checkpoint blockade overcomes therapy resistance in an immunologically cold model of advanced melanoma with dysfunctional T-cell receptor signalling

作者：E Armstrong, M. Chiu, Shane Foo, Lizzie Appleton, Pablo Nenclares, Anton Patrikeev, Nitya Mohan, Martin McLaughlin, Galabina Bozhanova, Julia Hoebart, Victoria Roulstone, Emmanuel C. Patin, Malin Pedersen, Joan Kyula, Masahiro Ono, Fiona Errington‐Mais, John C. Bell, Kevin J. Harrington, Alan Melcher, Victoria A. Jennings · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2024 · DOI：10.1136/jitc-2024-009443 · 被引用次数：15 · 研究领域：Virus-based gene therapy research、Immunotherapy and Immune Responses、CAR-T cell therapy research

BACKGROUND: Over the past decade, cancer immunotherapies have revolutionized the treatment of melanoma; however, responses vary across patient populations. Recently, baseline tumor size has been identified as an independent prognostic factor for overall survival in patients with melanoma receiving immune checkpoint inhibitors. MG1 is a novel oncolytic agent with broad tumor tropism that has recently entered early-phase clinical trials. The aim of this study was to characterize T-cell responses in human and mouse melanoma models following MG1 treatment and to establish if features of the tumor immune microenvironment (TIME) at two distinct tumor burdens would impact the efficacy of oncolytic virotherapy. METHODS: Human three-dimensional in vitro priming assays were performed to measure antitumor and antiviral T-cell responses following MG1 infection. T-cell receptor (TCR) sequencing, T2 killing assay, and peptide recall assays were used to assess the evolution of the TCR repertoire, and measure specific T-cell responses, respectively. In vivo, subcutaneous 4434 melanomas were characterized using RNA sequencing, immunohistochemistry, and flow cytometry. The effectiveness of intratumoral MG1 was assessed in advancing 4434 tumors and the generation of antitumor and antiviral T cells measured by splenocyte recall assays. Finally, combination MG1 and programmed cell death protein-1 antibody (αPD-1) therapy was investigated in advanced 4434 tumors. RESULTS: MG1 effectively supported...