Open AccessPrecision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits
Author(s) -
Kole T. Roybal,
Levi J. Rupp,
Leonardo Morsut,
Whitney J. Walker,
Krista A. McNally,
Jason S. Park,
Wendell A. Lim
Publication year - 2016
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2016.01.011
Subject(s) - antigen , chimeric antigen receptor , biology , bystander effect , antigen presenting cell , cytotoxic t cell , microbiology and biotechnology , immunology , receptor , t cell , cancer research , immune system , in vitro , genetics
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 ABSTRACT.
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