肿瘤细胞治疗研究
英文原题：Multi-armored allogeneic MUC1 CAR T cells enhance efficacy and safety in triple-negative breast cancer.
实体瘤，如三阴性乳腺癌（TNBC），由于细胞异质性、缺乏肿瘤特异性抗原以及免疫抑制性肿瘤微环境（TME），在生物学上具有复杂性。
实体瘤，如三阴性乳腺癌（TNBC），由于细胞异质性、缺乏肿瘤特异性抗原以及免疫抑制性肿瘤微环境（TME），在生物学上较为复杂。这些挑战限制了嵌合抗原受体（CAR）T细胞的疗效，凸显了装甲化的重要性。在实体癌中，局限性肿瘤肿块允许替代给药途径，例如瘤内递送，有可能提高疗效和安全性，但可能不利于转移部位的治疗。我们采用一种多层CAR T细胞工程策略，使各特性之间产生协同作用，展示了装甲化MUC1 CAR T细胞的细胞毒活性增强，这些细胞具备PD1 KO、肿瘤特异性白介素-12释放以及针对TNBC TME的TGFBR2 KO特性。瘤内治疗有效减少了远处肿瘤，提示在转移部位保留了抗原识别获益。总体而言，我们提供了临床前证据，证明装甲化非异体反应性MUC1 CAR T细胞在富含TGFB1和PD-L1的TME中，在局部和远处部位均大幅降低高TNBC肿瘤负荷，同时保持安全性。
Solid tumors, such as triple-negative breast cancer (TNBC), are biologically complex due to cellular heterogeneity, lack of tumor-specific antigens, and an immunosuppressive tumor microenvironment (TME). These challenges restrain chimeric antigen receptor (CAR) T cell efficacy, underlining the importance of armoring. In solid cancers, a localized tumor mass allows alternative administration routes, such as intratumoral delivery with the potential to improve efficacy and safety but may compromise metastatic-site treatment. Using a multi-layered CAR T cell engineering strategy that allowed a synergy between attributes, we show enhanced cytotoxic activity of MUC1 CAR T cells armored with PD1 KO , tumor-specific interleukin-12 release, and TGFBR2 KO attributes catered towards the TNBC TME. Intratumoral treatment effectively reduced distant tumors, suggesting retention of antigen-recognition benefits at metastatic sites. Overall, we provide preclinical evidence of armored non-alloreactive MUC1 CAR T cells greatly reducing high TNBC tumor burden in a TGFB1- and PD-L1-rich TME both at local and distant sites while preserving safety.
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