Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade

作者：Fei Ju, Yong Luo, Chaolong Lin, Xian Jia, Zilong Xu, Rui Tian, Yanhua Lin, Min Zhao, Ya‐Ting Chang, Xiaoxuan Huang, Shaopeng Li, Wenfeng Ren, Yaning Qin, Mengqin Yu, Jizong Jia, Jinle Han, Wenxin Luo, Jun Zhang, Guo Fu, Xiangzhong Ye, Chenghao Huang, Ningshao Xia · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2022-004762 · 被引用次数：77 · 研究领域：Virus-based gene therapy research、CAR-T cell therapy research、Cancer Research and Treatments

Background Oncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies. Methods A tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF). Results The identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8 + T cell activity by augmenting the tumor infiltration of effector CD8 + T cells and est...