Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits

T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual-receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo—sparing single antigen “bystander” tumors while efficiently clearing combinatorial antigen “disease” tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors. [Display omitted] [Display omitted] •Engineering of AND-gate T cells activated only by dual antigen recognition•The synNotch receptor (senses antigen 1) induces CAR expression (senses antigen 2)•AND-gate T cells spare single antigen cells but kill dual antigen tumors in vivo•SynNotch/CAR circuits expand set of antigens that can be targeted by immunotherapy T cells engineered with dual-receptor circuits that recognize combinations of antigens can efficiently kill target tumor cells in vivo, while sparing bystander cells.