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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 Feb 3

PMID 26830879

Citations 480

Authors

Kole T Roybal

Levi J Rupp

Leonardo Morsut

Whitney J Walker

Krista A McNally

Jason S Park

Wendell A Lim

Affiliations

Soon will be listed here.

Abstract

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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