State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China.
Yangshengtang Co., Ltd, Hangzhou, China.
J Immunother Cancer. 2022 Jun;10(6). doi: 10.1136/jitc-2022-004762.
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.
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).
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 establishment of memory CD8 T cells and reducing associated CD8 T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8 T cells and high levels of CTLA-4 Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.
Localized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.
溶瘤病毒 (OVs) 能够使肿瘤微环境 (TME) 发炎，并引发浸润性肿瘤特异性 T 细胞反应。然而，OV 治疗会对肿瘤中的癌症免疫设定点产生负面影响，从而减弱抗肿瘤免疫反应，这表明有必要剖析病毒治疗肿瘤的免疫图谱，并开发新策略来最大程度地发挥 OV 的潜力。本研究旨在探讨靶向 PD-1 的单链可变片段 (scFv) 武装 OV 对 TME 的影响，并最终克服局部免疫抑制，使肿瘤对免疫疗法敏感。
设计了一种肿瘤选择性溶瘤单纯疱疹病毒载体，该载体编码针对人类 PD-1 的人源化 scFv（hPD-1scFv）（YST-OVH）。在多种治疗性小鼠模型中探索了 YST-OVH 的抗肿瘤功效。在非人类灵长类动物中评估了 YST-OVH 的神经毒性和安全性。使用时间飞行流式细胞术（CyTOF）剖析了 YST-OVH 治疗中涉及的 TME 中的精确动力学。
鉴定出的 hPD-1scFv 显示出优越的 T 细胞激活活性。YST-OVH 通过局部递送 hPD-1scFv，促进了已建立癌症的人源化 PD-1 小鼠模型中的全身抗肿瘤免疫。使用 CyTOF 对肿瘤进行免疫谱分析显示，YST-OVH 的抗肿瘤效果增强，主要依赖于 CD8 T 细胞活性，通过增加效应 CD8 T 细胞在肿瘤中的浸润，建立记忆 CD8 T 细胞并减少相关 CD8 T 细胞衰竭。此外，YST-OVH 治疗改变了肿瘤的癌症免疫设定点，同时耗尽的 CD8 T 细胞上共表达 CTLA-4 和 TIM-3，以及高水平的 CTLA-4 Treg 细胞。通过增加肿瘤免疫原性并激活抗肿瘤适应性免疫反应，联合使用抗 CTLA-4 或抗 TIM-3 的方法进一步提高了疗效。此外，该治疗策略在非人类灵长类动物中没有显示出神经毒性并且耐受性良好。在携带人类癌细胞的人源化小鼠中也观察到了肿瘤内表达 hPD-1scFv 的益处。
通过工程化 YST-OVH 局部递送达 PD-1 抑制剂是一种高效且安全的癌症免疫疗法策略。YST-OVH 还与 CTLA-4 或 TIM-3 阻断协同作用，增强了对癌症的免疫反应。这些数据为进一步临床评估这种新型治疗方法提供了强有力的依据。
