- 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;
- Lim, Wendell A
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.