Synergically enhanced anti-tumor immunity of in vivo panCAR by circRNA vaccine boosting
Yanyan Wang, Liangru Lin, Xinyue Wang, Jing Li, Qian Pan, Haomeng Kou, Jie Yin, Fei Gao, Xinyuan Liao, Chenchen Zhang, Qimeng Yin, Chengzhi Zhao, Xinyang Li, Jinzhong Lin, Yichi Xu, Min Qiu, Dan Luo, Liang Qu
Abstract
Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic malignancies, but it still faces challenges, including high costs, a time-consuming manufacturing process, and the necessity of lymphodepletion. Here, we generate circular RNAs (circRNAs) encoding CAR proteins, referred to as circRNA CAR , which mediates remarkable tumor killing in human primary T cells. We demonstrate that circRNA CAR , delivered with immunocyte-tropic lipid nanoparticles (LNPs), can form in vivo panCAR cells (CAR-T, CAR-natural killer [NK], and CAR-macrophage), significantly inhibit tumor growth, and reshape the tumor microenvironment in mice. Importantly, combining in vivo panCAR with circRNA-based vaccines encoding the corresponding HER2 antigens exhibits synergistically enhanced anti-tumor immunity. Notably, circRNA CAR can in return boost the level of vaccination-elicited HER2-specific antibodies, mediating effective killing of tumor cells by macrophages. In combination with vaccination, in vivo panCAR demonstrates a synergistic enhancement of anti-tumor immunity across various mouse models, thereby establishing a framework for the synergistic in vivo panCAR-VAC immunotherapy.