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.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIzN2IxYWZiODQ0YTk2ODZiMGIwMGZiYjBkNjIzMmJiMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc5MjU5OTYzfQ.qvhC9J7Ww3K1_H610RIuAEOog3MUQmMnlOU4VKp2gYBCk-Rezlj1ZUfu8vqze2BG_QlqFpHLTfprbhELpQRAA9akAY5pnQ_BMaNGz4mVqwWSOJQMASEawDn4xahRJ7cDQo4pCXtnoPXwosxrqoWDXetsCdeTGnYE9sb03lYtpVlKCncdXiVA2ftRAm7nVVk6_7Ljnn-Ktwz65Eeb0SXry9C0UcCB7CzTFDHeL-aQSC6zL4GEEfmou06zSXBkrGGY6NFm3esBWDdHKvlO8Lu8_lROBtHFhFnYZP02aVN4GE11Zz22Htmg8e6SJ2VzeYrEXCR9Ci2gEQTtwJKXREMtxw(mp4, (54.96 MB) Download video