肿瘤细胞治疗研究
英文原题：Synergically enhanced anti-tumor immunity of in vivo panCAR by circRNA vaccine boosting.
Synergically enhanced anti-tumor immunity of in vivo panCAR by circRNA vaccine boosting.
嵌合抗原受体（CAR）T细胞疗法在治疗血液系统恶性肿瘤方面展现出前景，但仍面临挑战，包括高昂的成本、耗时的生产流程以及淋巴细胞清除的必要性。
嵌合抗原受体（CAR）T细胞疗法在治疗血液系统恶性肿瘤方面已显示出前景，但仍面临诸多挑战，包括成本高昂、生产流程耗时以及必须进行淋巴细胞清除。在此，我们生成了编码CAR蛋白的环状RNA（circRNA），称为circRNA CAR，其可在人原代T细胞中介导显著的肿瘤杀伤作用。我们证明，使用免疫细胞趋向性脂质纳米颗粒（LNP）递送的circRNA CAR可在小鼠体内形成panCAR细胞（CAR-T、CAR-自然杀伤[NK]细胞和CAR-巨噬细胞），显著抑制肿瘤生长，并重塑肿瘤微环境。重要的是，将体内panCAR与编码相应HER2抗原的circRNA疫苗联合使用，可协同增强抗肿瘤免疫。值得注意的是，circRNA CAR反过来可提高疫苗接种所引发的HER2特异性抗体水平，从而介导巨噬细胞对肿瘤细胞的有效杀伤。与疫苗接种联合使用时，体内panCAR在多种小鼠模型中均表现出对抗肿瘤免疫的协同增强作用，从而为体内panCAR-VAC协同免疫治疗建立了框架。
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.
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