Public Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Department of Lymphoma, Key Laboratory of Cancer Prevention and Therapy, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
J Drug Target. 2020 Nov;28(9):982-990. doi: 10.1080/1061186X.2020.1766473. Epub 2020 May 20.
Immunotherapies are changing the landscape of melanoma treatment, but 70% of the melanoma patients have no response to immune checkpoint inhibitors or oncolytic virus therapy. Thus, novel formulations are needed to improve the population benefiting from immunotherapy. Here, we report a combined therapeutic modality based on oncolytic virus nanovesicles composed of CaCl, oncolytic virus Ad5, lecithin and cholesterol (Lipo-Cap-Ad5) with immune checkpoint blockade (anti-PD-1 antibody). We investigated antitumour activity, systemic toxicity and mechanism of antitumour immune responses of Lipo-Cap-Ad5 + anti-PD-1 blockade, in a murine B16F10 tumour xenograft model. Through a series of studies, we found that Lipo-Cap-Ad5 in combination with anti-PD-1 blockade drastically reduced the tumour growth by 76.6%, and prolonged animals' survival with no obvious toxicity observed in heart, liver and kidney. The combination therapy facilitates tumour infiltration of effector CD4, CD8 T cells and increases secretion of TNF-α and IFN-γ. Therefore, Lipo-Cap-Ad5 in combination with anti-PD-1 blockade can potentiate and activate the immune system synergistically, ultimately creating a pro-inflammatory environment. These results suggest that combination immunotherapy of Lipo-Cap-Ad5 and anti-PD-1 blockade developed in this study has promising applications to enhance therapeutic efficacy with the potential of being translated into clinical practice.
免疫疗法正在改变黑色素瘤治疗的格局，但 70%的黑色素瘤患者对免疫检查点抑制剂或溶瘤病毒治疗没有反应。因此，需要新的制剂来提高受益于免疫疗法的人群。在这里，我们报告了一种基于由氯化钙、溶瘤病毒 Ad5、卵磷脂和胆固醇（Lipo-Cap-Ad5）组成的溶瘤病毒纳米囊泡与免疫检查点阻断（抗 PD-1 抗体）相结合的治疗方式。我们研究了 Lipo-Cap-Ad5+抗 PD-1 阻断在小鼠 B16F10 肿瘤异种移植模型中的抗肿瘤活性、全身毒性和抗肿瘤免疫反应的机制。通过一系列研究，我们发现 Lipo-Cap-Ad5 联合抗 PD-1 阻断可使肿瘤生长显著减少 76.6%，并延长动物的生存时间，而心脏、肝脏和肾脏未观察到明显的毒性。联合治疗促进效应性 CD4、CD8 T 细胞浸润，并增加 TNF-α 和 IFN-γ 的分泌。因此，Lipo-Cap-Ad5 联合抗 PD-1 阻断可以协同增强和激活免疫系统，最终创造一个促炎环境。这些结果表明，本研究中开发的 Lipo-Cap-Ad5 和抗 PD-1 阻断联合免疫疗法具有增强治疗效果的应用前景，并有可能转化为临床实践。
