A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo

Nat Cancer. 2023 Oct;4(10):1474-1490. doi: 10.1038/s43018-023-00642-8. Epub 2023 Oct 2.


Acute myeloid leukemia (AML), the most frequent leukemia in adults, is driven by recurrent somatically acquired genetic lesions in a restricted number of genes. Treatment with tyrosine kinase inhibitors has demonstrated that targeting of prevalent FMS-related receptor tyrosine kinase 3 (FLT3) gain-of-function mutations can provide significant survival benefits for patients, although the efficacy of FLT3 inhibitors in eliminating FLT3-mutated clones is variable. We identified a T cell receptor (TCR) reactive to the recurrent D835Y driver mutation in the FLT3 tyrosine kinase domain (TCRFLT3D/Y). TCRFLT3D/Y-redirected T cells selectively eliminated primary human AML cells harboring the FLT3D835Y mutation in vitro and in vivo. TCRFLT3D/Y cells rejected both CD34+ and CD34- AML in mice engrafted with primary leukemia from patients, reaching minimal residual disease-negative levels, and eliminated primary CD34+ AML leukemia-propagating cells in vivo. Thus, T cells targeting a single shared mutation can provide efficient immunotherapy toward selective elimination of clonally involved primary AML cells in vivo.

MeSH terms

  • Adult
  • Animals
  • Gain of Function Mutation
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / therapy
  • Mice
  • Mutation
  • Protein-Tyrosine Kinases* / genetics
  • Receptors, Antigen, T-Cell / genetics
  • fms-Like Tyrosine Kinase 3 / genetics


  • Protein-Tyrosine Kinases
  • Receptors, Antigen, T-Cell
  • fms-Like Tyrosine Kinase 3
  • FLT3 protein, human