Hyrenius-Wittsten et al. identified alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, and engineered synthetic Notch (synNotch) CAR combinatorial antigen circuit T cells using ALPPL2 as a priming antigen and melanoma cell adhesion molecule (MCAM), mesothelin, or HER2 as CAR targets. Compared to conventional CAR T cells, ALPPL2 synNotch CAR circuit T cells exhibited a T stem cell memory-like phenotype with reduced tonic signalling, prevented detrimental T cell differentiation before antigen exposure, and showed superior antitumor efficacy and in vivo persistence.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 9
Author Info: (1) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA. (2) Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94110, USA. (3) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (4) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (5) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (8) Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA. kole.roybal@ucsf.edu bin.liu@ucsf.edu. Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94110, USA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. (9) Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. kole.roybal@ucsf.edu bin.liu@ucsf.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Gladstone-UCSF Institute for Genomic Immunology, San Francisco, CA 94158, USA. UCSF Cell Design Institute, San Francisco, CA 94158, USA.
