Abstract
Small molecule–activated chimeric antigen receptors (CAR) allow for regulation of T-cell activity.
Major finding: Small molecule–activated chimeric antigen receptors (CAR) allow for regulation of T-cell activity.
Concept: T cells made to express ON-switch CARs require both tumor antigen and a small molecule for activation.
Impact: Small-molecule control of CAR T cells allows for reduced toxicity in tumor immunotherapy.
The use of engineered T cells represents a promising avenue for cancer immunotherapy. T cells can be engineered to express synthetic chimeric antigen receptors (CAR), which are comprised of a tumor antigen–specific extracellular antibody domain and intracellular T-cell signaling domains and costimulatory receptors. Binding to tumor antigen induces production of antitumor cytokines, therapeutic T-cell proliferation, and killing of antigen-expressing tumor cells. However, these therapies can lead to severe toxicities due to cross-reactivity and excessive immune responses. To address these limitations, Wu and colleagues developed an “ON-switch” CAR that allows for more precise control and titration of the activity of engineered therapeutic T cells. In this split receptor system, the antigen-binding domain only heterodimerized with the intracellular signaling component in the presence of a small-molecule, such as the rapamycin analogue AP21967 (rapalog). Cytokine production in response to target cell stimulation was as strong with the ON-switch CAR as with a conventional CAR, and required both the antigen and small-molecule. In addition, the presence of antigen and small molecule induced CD4+ T-cell proliferation and CD8+ T cell–mediated cytotoxicity of antigen-expressing tumor cells. Furthermore, the ON-switch CAR was also effective in vivo in a mouse xenograft model; injection of ON-switch CAR T cells resulted in small molecule–dependent depletion of target CD19+ tumor cells and displayed similar efficacy as conventional CAR T cells. The findings suggest that ON-switch CAR T cells may allow for precise regulation of T cell activity and for control of the timing and location of tumor cell killing. Moreover, the ON-switch CAR strategy for T-cell immunotherapy in cancer may reduce toxicity, making it a potentially safer option for patients.
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