Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy
Rong Duan, Philip Milton, Chutamath Sittplangkoon, Xin Liu, Zhining Sui, Brendan F. Boyce, Zhenqiang Yao
Abstract
Abstract 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. TNF α 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 α to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNF α through an inactive adoptive cell in combination with an IAP antagonist. Methods Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNF α , and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNF α (M-DCs TNF ). The efficacy of M-DCs TNF 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-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. Conclusion An adoptive cell targeting delivery of TNF α 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.