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Synthetic cytokine circuits that drive T cells into immune-excluded tumors

Authors
Greg M. Allen,Nicholas W. Frankel
Nishith R. Reddy,Hersh K. Bhargava,Maia A. Yoshida,Sierra R. Stark,Megan Purl,Jungmin Lee,Jacqueline L. Yee,Wei Yu,Aileen W. Li,K. Christopher Garcia,Hana El-Samad,Kole T. Roybal,Matthew H. Spitzer,Wendell A. Lim,Greg Allen,Nicholas Frankel,Nishith Reddy,Hersh Bhargava,Maia Yoshida,Sierra Stark,Jacqueline Yee,Aileen Li,K. Garcia,Hana El‐Samad,Kole Roybal,Matthew Spitzer
+26 authors
,Wendell Lim
Journal
Published
Dec 16, 2022
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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.

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