Synthetic cytokine circuits that drive T cells into immune-excluded tumors
Greg M. Allen, Nicholas 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 García, Hana El‐Samad, Kole T. Roybal, Matthew H. Spitzer, Wendell A. Lim
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.