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

Ali, M.; Giannakopoulou, E.; Li, Y.Q.; Lehander, M.; Culleton, S.V.; Yang, W.W.; Knetter, C.; Odabasi, M.C.; Bollineni, R.C.; Yang, X.B.; Foldvari, Z.; Boschen, M.L.; Taraldsrud, E.; Stronen, E.; Toebes, M.; Hillen, A.; Mazzi, S.; Ru, A.H. de; Janssen, G.M.C.; Kolstad, A.; Tjonnfjord, G.E.; Lie, B.A.; Griffioen, M.; Lehmann, S.; Osnes, L.T.; Buechner, J.; Garcia, K.C.; Schumacher, T.N.; Veelen, P.A. van; Leisegang, M.; Jacobsen, S.E.W.; Woll, P.; Olweus, J.

doi:doi:10.1038/s41587-021-01089-x

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...Show moreUnlike 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.Engineered T cells kill leukemic cells with little off-target toxicity.Show less

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