肿瘤细胞治疗研究
英文原题：Preclinical efficacy of multi-targeting mRNA-based CAR T cell therapy in resection models of glioblastoma.
Preclinical efficacy of multi-targeting mRNA-based CAR T cell therapy in resection models of glioblastoma.
传统的病毒载体嵌合抗原受体（CAR）T 细胞疗法已攻克多种血液系统恶性肿瘤，可实现长达十年的缓解，但在实体瘤面前仍举步维艰。
传统病毒载体介导的嵌合抗原受体（CAR）T细胞疗法已使多种血液系统恶性肿瘤获得长达十年的缓解，但治疗实体瘤仍面临困难。通过电穿孔或脂质纳米颗粒（LNP）递送编码CAR的mRNA进行非病毒工程化改造，可实现高效但短暂的CAR表达，这使现有临床前模型能否充分评估mRNA CAR-T细胞受到质疑。本研究提出一种独特的三管齐下方法，将mRNA CAR-T细胞、针对胶质母细胞瘤（GBM）相关受体的多靶点策略，以及最大程度手术切除相结合，建立一个新颖且易于转化的平台，用于临床前评估mRNA CAR-T实体瘤疗法。我们对采用不同扩增条件、mRNA递送方式或联合策略制备的mRNA CAR-T细胞开展了直接的体外和体内比较分析。除具有强效体外细胞毒性外，研究还揭示了抗肿瘤疗效窗口；在最大程度手术切除后接受多价CAR-T细胞（MVCAR）局部注射的GBM异种移植小鼠模型中，实现了稳健且持久的完全缓解。扩增5天的T细胞疗效显著优于静息T细胞。值得注意的是，在原位GBM切除模型中，MVCAR T细胞优于混合表达相同CAR scFv组合的CAR-T细胞（CARPool）。
Traditional viral-based chimeric antigen receptor (CAR) T cell therapies have vanquished multiple blood malignancies with decade-long remissions yet struggle against solid tumors. Nonviral engineering of CAR T cells via electroporation or lipid nanoparticle (LNP) delivery of CAR-encoding mRNA results in highly efficient yet transient CAR expression, challenging the adequacy of available preclinical models for mRNA-based CAR T cell evaluation. This study presents a unique three-pronged approach that combines mRNA-based CAR T cells, multi-targeting of glioblastoma (GBM)-associated receptors, and maximal surgical resection as a novel and readily translatable platform for preclinical evaluation of mRNA-based CAR T cells against solid tumors. We performed head-to-head in vitro and in vivo analyses of mRNA-based CAR T cells generated using different expansion conditions, mRNA delivery methods, or combination approaches. Besides potent in vitro cytotoxicity, our findings unveil a therapeutic window of anti-tumor efficacy, as well as robust and durable complete remissions in xenograft mouse models of GBM receiving maximal surgical resection and locoregional injections of multivalent CAR T cells (MVCAR). Such efficacies were significantly better in 5-day expanded versus quiescent T cells. Interestingly, MVCAR T cells were superior to pooled CAR T cells (CARPool) expressing the same CAR scFv combinations in an orthotopic resection model of GBM.
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