SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models.

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.

• Authors: Axel Hyrenius-Wittsten, Yang Su, Minhee Park, Julie M Garcia, Josef Alavi, Nathaniel Perry, Garrett Montgomery, Bin Liu, Kole T Roybal
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 591 (04 28 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33910981 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Msln protein, mouse
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen
• Mesothelin

Topics

• Cell Line, Tumor
• Female
• Humans
• Immunotherapy, Adoptive
• Mesothelin
• Mice
• Placenta
• Pregnancy
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen
• Xenograft Model Antitumor Assays