1. Synthetic cytokine circuits that drive T cells into immune-excluded tumors
- Author
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Allen, Greg M, Frankel, Nicholas W, Reddy, Nishith R, Bhargava, Hersh K, Yoshida, Maia A, Stark, Sierra R, Purl, Megan, Lee, Jungmin, Yee, Jacqueline L, Yu, Wei, Li, Aileen W, Garcia, K Christopher, El-Samad, Hana, Roybal, Kole T, Spitzer, Matthew H, and Lim, Wendell A
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Inflammatory and immune system ,Humans ,Immunotherapy ,Adoptive ,Interleukin-2 ,Neoplasms ,Receptors ,Antigen ,T-Cell ,T-Lymphocytes ,Tumor Microenvironment ,Animals ,Mice ,Receptors ,Chimeric Antigen ,Cell Engineering ,Receptors ,Notch ,Immunosuppression Therapy ,General Science & Technology - Abstract
Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.
- Published
- 2022