A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo.
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Giannakopoulou E, Lehander M, Virding Culleton S, Yang W, Li Y, Karpanen T, Yoshizato T, Rustad EH, Nielsen MM, Bollineni RC, Tran TT, Delic-Sarac M, Gjerdingen TJ, Douvlataniotis K, Laos M, Ali M, Hillen A, Mazzi S, Chin DWL, Mehta A, Holm JS, Bentzen AK, Bill M, Griffioen M, Gedde-Dahl T, Lehmann S, Jacobsen SEW, Woll PS, Olweus J
Nat Cancer - (-) - [2023-10-02; online 2023-10-02]
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.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 37783807
DOI 10.1038/s43018-023-00642-8
Crossref 10.1038/s43018-023-00642-8
pii: 10.1038/s43018-023-00642-8