Cancer cells are specifically targeted by requiring two antigens to activate therapeutic T cells.
Major finding: Cancer cells are specifically targeted by requiring two antigens to activate therapeutic T cells.
Approach: A dual-receptor T-cell system was created in which synNotch receptor activation drives CAR expression.
Impact: Dual antigen–activated therapeutic T cells may reduce off-target effects of T-cell therapy.
Therapeutic T cells expressing chimeric antigen receptors (CAR) have promise in tumor immunotherapy. However, few antigens are absolutely tumor specific; thus, nonmalignant cells are also targeted, resulting in off-target effects. In order to achieve more precise tumor cell killing, Roybal and colleagues engineered a combinatorially activated T-cell circuit based on a synthetic Notch receptor (synNotch) developed by Morsut, Roybal, and colleagues. The synNotch receptors are modular receptors in which the Notch cleavage domain is fused to a select extracellular tumor antigen–recognizing receptor and an intracellular transcription factor. Upon antigen binding to the synNotch receptor, the transcription factor is cleaved and induces the expression of a specified CAR, which binds to a second antigen to activate the T cell. Thus, the presence of two tumor antigens is required to active the T cells. Jurkat T cells engineered with an αCD19 synNotch and mesothelin CAR were co-cultured with leukemia cells expressing CD19, mesothelin, or both antigens. As expected, T cells were activated only when both antigens were present. The dual system was also effective in primary CD4+ and CD8+ T cells using the αGFP synNotch/CD19 CAR. Both types of T cells were activated only when exposed to target cells expressing both surface antigens. To further validate this system in vivo, mice were xenografted with CD19+ tumors with and without GFP, and were injected with primary CD4+ and CD8+ T cells modified with αGFP synNotch/CD19 CAR. Mice with tumors expressing both GFP and CD19 survived and the tumors were completely cleared. However, tumors expressing only CD19 or only GFP continued to grow. Taken together, these data indicate that the synNotch–CAR system allows for successful engineering of therapeutic T cells activated only in the presence of two tumor antigens. This approach may be effective in reducing the off-target effects of tumor T-cell immunotherapy, and may be used with diverse tumor antigens.
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- ©2016 American Association for Cancer Research.