Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters
Hyung Bae Park, Ki Hyun Kim, Ju Hwan Kim, Sang Il Kim, Yu Mi Oh, Miseung Kang, Seoho Lee, Siwon Hwang, Hyeonmin Lee, Tae Jin Lee, S H Park, Ji‐Eun Lee, Ga Ram Jeong, Dong Hyun Lee, Hyewon Youn, Eun Young Choi, Woo‐Chan Son, Sang J. Chung, Junho Chung, Kyungho Choi
Abstract
Chimeric antigen receptor T (CAR-T) cells show remarkable efficacy for some hematological malignancies. However, CAR targets that are expressed at high level and selective to tumors are scarce. Several strategies have been proposed to tackle the on-target off-tumor toxicity of CAR-T cells that arise from suboptimal selectivity, but these are complicated, with many involving dual gene expression for specificity. In this study, we show that switchable CAR-T cells with a tumor targeting adaptor can mitigate on-target off-tumor toxicity against a low selectivity tumor antigen that cannot be targeted by conventional CAR-T cells, such as CD40. Our system is composed of anti-cotinine murine CAR-T cells and cotinine-labeled anti-CD40 single chain variable fragments (scFv), with which we show selective tumor killing while sparing CD40-expressing normal cells including macrophages in a mouse model of lymphoma. Simple replacement of the tumor-targeting adaptor with a suicidal drug-conjugated tag may further enhance safety by enabling permanent in vivo depletion of the switchable CAR-T cells when necessary. In summary, our switchable CAR system can control CAR-T cell toxicity while maintaining therapeutic efficacy, thereby expanding the range of CAR targets. The therapeutic success of CAR-T cells depends on the availability of selective and high-density targets, which limits their applicability due to on-target off-tumor toxicity. Here authors overcome this limitation in a mouse model of immune therapy in which an adaptor is an epitope-tagged single chain variable fragment targeting the tumour antigen, and the CAR-T cells are targeting the epitope, thus enabling a precise dose-switch.