T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes

Nat Biotechnol. 2022 Apr;40(4):488-498. doi: 10.1038/s41587-021-01089-x. Epub 2021 Dec 6.


Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80-94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

Publication types

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

MeSH terms

  • Animals
  • DNA Nucleotidylexotransferase*
  • Hematopoietic Stem Cells
  • Lymphocytes
  • Mice
  • Receptors, Antigen, T-Cell / genetics
  • T-Lymphocytes*


  • Receptors, Antigen, T-Cell
  • DNA Nucleotidylexotransferase