Two limitations of oncolytic adenovirus (OA) cancer therapy are achieving therapeutic doses in the tumor with systemic injection and overcoming PD-1-mediated suppression with continued OA treatment. Chen and Chen et al. addressed these challenges by creating an OA-T cell chimera (ONCOTECH). OAs were engineered to express a Cas9 system targeting the PDL1 gene, and coated with cell membranes designed to express T cell-specific antigens, allowing physical conjugation to T cells (CARs or engineered TCRs). In a mouse melanoma model, a single IV dose of ONCOTECH resulted in 80% survival over 70 days and a 50% reduction in PD-L1 expression.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. National Key Laboratory of A
Author Info: (1) College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China. (2) College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. (3) State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China. School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China. (4) State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China. (5) State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China. School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, China. (6) College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. pingy@zju.edu.cn. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China. pingy@zju.edu.cn. National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China. pingy@zju.edu.cn.
