嵌合抗原受体树突状细胞靶向递送单一杀肿瘤因子用于癌症免疫治疗

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. TNF 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 TNF to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNF through an inactive adoptive cell in combination with an IAP antagonist.

Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNF , and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNF (M-DCs TNF ). The efficacy of M-DCs TNF in recognizing and treating breast cancer was tested in vitro and in vivo.

Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCs TNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCs TNF 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-DCs TNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.

An adoptive cell targeting delivery of TNF 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.