HLA-independent T cell receptors for targeting tumors with low antigen density

Nat Med. 2022 Feb;28(2):345-352. doi: 10.1038/s41591-021-01621-1. Epub 2022 Jan 13.


Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

Publication types

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

MeSH terms

  • Animals
  • Antigens, CD19
  • Histocompatibility Antigens
  • Humans
  • Immunotherapy, Adoptive
  • Leukemia, Myeloid, Acute*
  • Mice
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen* / metabolism
  • Xenograft Model Antitumor Assays


  • Antigens, CD19
  • Histocompatibility Antigens
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen