期刊
SCIENCE
卷 350, 期 6258, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aab4077
关键词
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资金
- Jane Coffin Childs Memorial Fund [A121505]
- NIH [PN2 EY016546, P50 GM081879, R01 GM055040, R01 CA196277, F32 GM101782]
- HHMI
There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed ON-switch CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control.
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