Journal
CELL
Volume 164, Issue 4, Pages 770-779Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.01.011
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Funding
- Jane Coffin Childs Memorial Fund Postdoctoral Fellowship [A121505]
- Human Frontiers of Science Program Postdoctoral Fellowship
- NIH [PN2 EY016546, P50GM081879, R01 GM055040, R01 CA196277]
- Howard Hughes Medical Institute
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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.
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