Ali and Giannakopolou et al. developed a T cell-based therapy to target TdT, an intracellular antigen upregulated transiently during lymphocyte development, but overexpressed in many leukemias. Through mass spectrometry, they found TdT-derived peptides capable of binding the common HLA-A2 allele, then identified reactive TCR clones. T cells transduced with these TCRs recognized only cells expressing both TdT and HLA-A2, spared normal lymphocytes and progenitors, and effectively treated NSG mice engrafted with HLA-A2+TdT+ leukemia lines or primary xenograft B-ALL, even when the T cells and ALL were non HLA-matched.
Contributed by Alex Najibi
ABSTRACT: 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.