NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.
NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.
复制标题
DOI：
10.1158/2643-3230.bcd-20-0208
复制
发表时间：
2021-11
影响因子：
11.2
通讯作者：
Mackall CL
中科院分区：
文献类型：
--
作者：
Richards RM;Zhao F;Freitas KA;Parker KR;Xu P;Fan A;Sotillo E;Daugaard M;Oo HZ;Liu J;Hong WJ;Sorensen PH;Chang HY;Satpathy AT;Majzner RG;Majeti R;Mackall CL
CD93 CAR T细胞在临床前模型中消除AML而不靶向造血祖细胞，并且NOT门控CAR工程化策略减轻了对内皮细胞的靶向、脱肿瘤毒性。嵌合抗原受体（CAR）T细胞有望用于治疗急性髓性白血病（AML），但最佳靶点仍有待确定。我们证明了从新型人源化CD93特异性结合剂工程化的CD93 CAR T细胞在体外和体内有效地杀死AML，但保留造血干细胞和祖细胞（HSPC）。在鼠模型中没有观察到毒性，但CD93在人内皮细胞上表达，并且CD93 CAR T细胞识别并杀死内皮细胞系。我们鉴定了在内皮细胞上具有重叠表达的其他AML CAR T细胞靶标，特别是在促炎细胞因子的背景下。为了解决内皮特异性交叉反应性的挑战，我们提供了在相关模型系统中规避内皮细胞毒性的NOT门控CD93 CAR T细胞的概念证明。我们还通过分析AML和内皮细胞在基线和暴露于促炎细胞因子后的转录组来确定组合靶向的候选者。CD93 CAR T细胞消除AML和备用HSPC，但对内皮细胞产生靶向、肿瘤外毒性。我们展示了其他AML靶点在内皮细胞上的共表达，引入了一种新的NOT门控策略来减轻内皮细胞毒性，并展示了使用高维转录组学分析来合理设计组合免疫疗法。参见Velasquez和Gottschalk的相关评论。 这篇文章在本期专题中突出显示，
CD93 CAR T cells eliminate AML in preclinical models without targeting hematopoietic progenitor cells, and a NOT-gated CAR engineering strategy mitigates on-target, off-tumor toxicity to endothelial cells. Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR T cells engineered from a novel humanized CD93-specific binder potently kill AML in vitro and in vivo but spare hematopoietic stem and progenitor cells (HSPC). No toxicity is seen in murine models, but CD93 is expressed on human endothelial cells, and CD93 CAR T cells recognize and kill endothelial cell lines. We identify other AML CAR T-cell targets with overlapping expression on endothelial cells, especially in the context of proinflammatory cytokines. To address the challenge of endothelial-specific cross-reactivity, we provide proof of concept for NOT-gated CD93 CAR T cells that circumvent endothelial cell toxicity in a relevant model system. We also identify candidates for combinatorial targeting by profiling the transcriptome of AML and endothelial cells at baseline and after exposure to proinflammatory cytokines. CD93 CAR T cells eliminate AML and spare HSPCs but exert on-target, off-tumor toxicity to endothelial cells. We show coexpression of other AML targets on endothelial cells, introduce a novel NOT-gated strategy to mitigate endothelial toxicity, and demonstrate use of high-dimensional transcriptomic profiling for rational design of combinatorial immunotherapies. See related commentary by Velasquez and Gottschalk, . This article is highlighted in the In This Issue feature,