背景:嵌合抗原受体(CAR)-T细胞已用于通过产生多种细胞因子来治疗血癌。然而,它们不能有效治疗实体癌,并可能导致严重的副作用,包括细胞因子释放综合征。TNFα是一种肿瘤杀伤细胞因子,但是它显着增加了cIAP1和cIAP2的蛋白水平,cIAP1和cIAP2是E3泛素连接酶凋亡抑制蛋白(IAP)家族的成员,可限制caspase诱导的凋亡。IAP拮抗剂对IAP蛋白的降解不能有效地杀死癌细胞,但能够使TNFα强烈诱导癌细胞凋亡。通过与IAP拮抗剂组合的无活性过继细胞靶向递送TNFα将是治疗癌症的有希望的方法。
方法:人树突状细胞(DCs)被工程化以表达单个肿瘤杀伤因子,TNFα,和膜锚定粘蛋白1抗体scFv,命名为表达TNFα的粘蛋白1定向DC(M-DCsTNF)。在体外和体内测试了M-DCsTNF在识别和治疗乳腺癌中的功效。
结果:粘蛋白1在多种人类乳腺癌细胞系的表面高表达。M-DCsTNF与NSG小鼠骨中的MDA-MB-231细胞直接相关。M-DCsTNF加IAP拮抗剂,SM-164,但也不是一个人,显著诱导MDA-MB-231乳腺癌细胞凋亡,被TNF抗体阻断。重要的是,M-DCsTNF联合SM-164,但不是单独的SM-164,抑制NSG小鼠患者源性乳腺癌的生长。
结论:TNFα的过继性细胞靶向递送联合IAP拮抗剂是治疗乳腺癌的一种新的有效方法,并且可以扩展到治疗其他实体癌。与CAR-T细胞不同,这种新的过继细胞不被激活以产生各种各样的细胞因子,除了额外的过度表达的TNF,因此可以避免严重的副作用,如细胞因子释放综合征。
BACKGROUND: Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.
METHODS: Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF). The efficacy of M-DCsTNF in recognizing and treating breast cancer was tested in vitro and in vivo.
RESULTS: Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.
CONCLUSIONS: An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.