Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Immunol Res. 2023 Sep 1;11(9):1253-1265. doi: 10.1158/2326-6066.CIR-22-0879.
Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
基因工程、细胞毒性、过继转移的 T 细胞可定位于患者体内抗原阳性的癌细胞，但肿瘤异质性和多种免疫逃逸机制阻止了大多数实体瘤类型的消除。正在开发更有效、多功能的工程 T 细胞来克服实体瘤治疗的障碍，但这些高度修饰的细胞与宿主的相互作用知之甚少。我们之前在嵌合抗原受体 (CAR) T 细胞中设计了前药激活酶功能，赋予它们与传统 T 细胞细胞毒性正交的杀伤机制。这些递药细胞被称为合成酶武装杀伤细胞 (SEAKER)，在小鼠淋巴瘤异种移植模型中显示出疗效。然而，免疫缺陷异种移植物与如此复杂的工程 T 细胞的相互作用与免疫宿主中的相互作用不同，这使得人们无法理解这些生理过程如何影响治疗。在此，我们使用 T 细胞受体 (TCR) 工程化 T 细胞进行特异性靶向，将 SEAKER 细胞的作用谱扩展到用于治疗同源小鼠模型中的实体瘤黑色素瘤。我们证明 SEAKER 细胞可以特异性定位于肿瘤，并激活生物活性前药，尽管存在宿主免疫反应。我们还表明，TCR 工程 SEAKER 细胞在免疫宿主中有效，表明 SEAKER 平台适用于许多过继细胞疗法。
