TY - JOUR TI - SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models AU - Hyrenius-Wittsten, Axel AU - Su, Yang AU - Park, Minhee AU - Garcia, Julie M. AU - Alavi, Josef AU - Perry, Nathaniel AU - Montgomery, Garrett AU - Liu, Bin AU - Roybal, Kole T. T2 - Science Translational Medicine AB - Short circuiting solid tumors Two major hurdles in chimeric antigen receptor (CAR) T cell therapy for solid tumors are ensuring specificity to tumor cells without affecting healthy cells and avoiding tumor escape due to antigen loss. To address these challenges, Hyrenius-Wittsten et al. and Choe et al. developed synthetic Notch (synNotch)–CAR T cells targeting solid tumor antigens and used them to treat mouse models of mesothelioma, ovarian cancer, and glioblastoma. In both studies, the authors demonstrated that synNotch-CAR T cells were better at controlling tumors than traditional CAR T cells and did not result in toxicity or damage to healthy tissue. These results suggest that synNotch-CAR T cells may be an effective treatment strategy for solid tumors. The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells. SynNotch CAR circuits targeting specific solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion. SynNotch CAR circuits targeting specific solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion. DA - 2021/04/28/ PY - 2021 DO - 10.1126/scitranslmed.abd8836 DP - stm.sciencemag.org VL - 13 IS - 591 LA - en SN - 1946-6234, 1946-6242 UR - https://stm.sciencemag.org/content/13/591/eabd8836 Y2 - 2021/04/29/05:42:07 ER -