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

Cell. 2016 Feb 11;164(4):770-9. doi: 10.1016/j.cell.2016.01.011. Epub 2016 Jan 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • Antigens, Surface / immunology
  • Bystander Effect
  • Cell Communication
  • Cell Line, Tumor
  • Disease Models, Animal
  • GPI-Linked Proteins / metabolism
  • Humans
  • Immunotherapy / methods*
  • Jurkat Cells
  • Lymphocyte Activation
  • Mesothelin
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / therapy*
  • Receptors, Notch / metabolism
  • T-Lymphocytes / metabolism*


  • Antigens, CD19
  • Antigens, Surface
  • GPI-Linked Proteins
  • Receptors, Notch
  • Mesothelin