Oncolytic herpes virus G47Δ works synergistically with CTLA-4 inhibition via dynamic intratumoral immune modulation.

Abstract

Oncolytic virus therapy can increase the immunogenicity of tumors and remodel the immunosuppressive tumor microenvironment, leading to an increased antitumor response to immune-checkpoint inhibitors. Here, we investigated the therapeutic potential of G47Δ, a third-generation oncolytic herpes simplex virus type 1, in combination with immune-checkpoint inhibitors using various syngeneic murine subcutaneous tumor models. Intratumoral inoculations with G47Δ and systemic anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody administration caused an enhanced antitumor activity when combined and worked synergistically. Conversely, the efficacy of G47Δ in combination with anti-programmed cell death protein-1 (PD-1) antibody was equivalent to that of the anti-PD-1 antibody alone in all murine models examined. The combination of intratumoral G47Δ and systemic anti-CTLA-4 antibody was shown to recruit effector T cells into the tumor efficiently while decreasing regulatory T cells. Furthermore, a wide range of gene signatures related to inflammation, lymphoid lineage, and T cell activation was highly upregulated with the combination therapy, suggesting the conversion of immune-insusceptible tumors to immune susceptible. The therapeutic effect proved tumor specific and long lasting. Immune cell subset depletion studies demonstrated that CD4+ T cells were required for synergistic curative activity. The results depict the dynamics of immune modulation of the tumor microenvironment and provide a clinical rationale for using G47Δ with immune checkpoint inhibitors.

• Authors: Kotaro Sugawara, Miwako Iwai, Hirotaka Ito, Minoru Tanaka, Yasuyuki Seto, Tomoki Todo
• Journal: Molecular therapy oncolytics (Mol Ther Oncolytics) Vol. 22 Pg. 129-142 (Sep 24 2021) ISSN: 2372-7705 [Print] United States
• PMID: 34514094 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s).