T Cells Targeting TdT Selectively Kill Leukemic Lymphoblasts

Approximately 40% to 50% of patients relapse due to antigen loss after chimeric antigen receptor (CAR) T-cell therapy for acute B-lymphoblastic leukemia (B-ALL), while no current CAR T-cell therapies exist that effectively target malignant cells while sparing normal cells in acute T-lymphoblastic leukemia (T-ALL). Therefore, Ali, Giannakopoulou, and colleagues examined tumor-specific targets in both B-ALL and T-ALL through investigation of terminal deoxynucleotidyl transferase (TdT). TdT is expressed only during a narrow window in B- and T-cell differentiation and is overexpressed in ALL, making it an ideal immunotherapy target. In contrast to CARs, which can only recognize surface antigens, T-cell receptors (TCR) can recognize intracellular antigens when in complex with human leukocyte antigen (HLA) molecules. Two TdT-derived peptides—peptide-1 and peptide-3—were identified by mass spectrometry as naturally presented on HLA-A2, and to combat T-cell tolerance to self-antigens, these peptides were presented to HLA-A2–negative T cells on allogeneic HLA-A2, allowing for discovery of two highly sensitive TdT-reactive TCRs, T1 and T3. T cells transduced with T1 and T3 could only be activated in a HLA-A2–restricted and TdT-dependent manner, and T1 and T3 cells were not activated when in coculture with a panel of TdT-negative cell lines. Mice engrafted with B-cell leukemia cell lines exposed to T3 cells showed no tumor burden at the experimental endpoint with a similar result observed in mice engrafted with cells from patients with primary B-ALL. To determine whether T1 and T3 cells selectively recognize human ALL cells over normal B and T cells, T1 and T3 cells were cocultured with ALL patient samples also containing normal B and T cells. After 72 hours, T1 and T3 cells had only eliminated leukemic blasts while sparing normal T and B cells. Furthermore, T3 cell therapy had no effect on thymocytes in humanized CD34⁺ NSG mice treated with T3-autologous human T cells, demonstrating the lack of toxicity of T3 on normal lymphoid cells. In summary, this study demonstrates that T cells with TCRs recognizing TdT are an effective and tumor-specific immunotherapy for B- and T-ALL.

Ali M, Giannakopoulou E, Li Y, Lehander M, Culleton SV, Yang W, et al. T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes. Nat Biotechnol 2021 Dec 6 [Epub ahead of print].

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