Chen Yuxuan, Chen Xiaohong, Bao Weier, Liu Gang, Wei Wei, Ping Yuan
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
Nat Biotechnol. 2024 Dec;42(12):1876-1887. doi: 10.1038/s41587-023-02118-7. Epub 2024 Feb 9.
The efficacy of oncolytic adenoviruses (OAs) for cancer therapy has been limited by insufficient delivery to tumors after systemic injection and the propensity of OAs to induce the expression of immune checkpoints. To address these limitations, we use T cells to deliver OAs into tumors and engineer the OA to express a Cas9 system targeting the PDL1 gene encoding the immune checkpoint protein PD-L1. By cloaking OAs with cell membranes presenting T cell-specific antigens, we physically conjugated OAs onto T cell surfaces by antigen-receptor interaction. We tested the oncolytic virus-T cell chimera (ONCOTECH) via intravenous delivery in mouse cancer models, including models of melanoma, pancreatic adenocarcinoma, lung cancer and glioblastoma. In the melanoma model, the in vivo delivery of ONCOTECH resulted in a strong accumulation of OAs in tumor cells, where PD-L1 expression was reduced by 50% and the single administration of ONCOTECH enabled 80% survival over 70 days. Collectively, ONCOTECH represents a promising translational technology to combine virotherapy and cell therapy.
溶瘤腺病毒（OAs）用于癌症治疗的疗效受到全身注射后肿瘤递送不足以及OAs诱导免疫检查点表达倾向的限制。为了解决这些限制，我们利用T细胞将OAs递送至肿瘤，并对OA进行工程改造，使其表达靶向编码免疫检查点蛋白PD-L1的PDL1基因的Cas9系统。通过用呈现T细胞特异性抗原的细胞膜包裹OAs，我们通过抗原受体相互作用将OAs物理偶联到T细胞表面。我们在小鼠癌症模型中，包括黑色素瘤、胰腺腺癌、肺癌和胶质母细胞瘤模型中，通过静脉注射测试了溶瘤病毒-T细胞嵌合体（ONCOTECH）。在黑色素瘤模型中，ONCOTECH的体内递送导致OAs在肿瘤细胞中大量积累，其中PD-L1表达降低了50%，单次给予ONCOTECH可使70天内的生存率达到80%。总体而言，ONCOTECH代表了一种将病毒疗法和细胞疗法相结合的有前景的转化技术。
