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

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• T-cell receptors (TCRs) can target intracellular antigens presented by human leukocyte antigen (HLA) molecules, unlike chimeric antigen receptors.
• Terminal deoxynucleotidyl transferase (TdT) is a lymphoid-specific enzyme highly expressed in acute lymphoblastic leukemia (ALL).

Purpose of the Study:

• To investigate the efficacy of TCR-engineered T-cells targeting TdT for treating T- and B-cell acute lymphoblastic leukemia (ALL).
• To assess the safety profile of this TdT-specific immunotherapy in preclinical models.

Main Methods:

• TCR-engineered T-cells targeting TdT peptides presented by HLA-A*02:01 were generated.
• The efficacy and specificity of these T-cells were evaluated in vitro against primary ALL cells and in vivo using mouse models of disseminated B-ALL.
• The impact on normal hematopoietic cells was assessed in vitro and in humanized mice.

Main Results:

• TdT-specific TCR T-cells effectively eliminated primary T- and B-cell ALL cells in vitro.
• Significant tumor reduction was observed in mouse models of disseminated B-ALL.
• Normal T-cells, B-cells, and myeloid cells were spared in vitro and in vivo, indicating high specificity.
• TdT's transient expression in normal lymphoid development limits on-target toxicity.

Conclusions:

• TCR-modified T-cells targeting TdT represent a promising immunotherapy for B-cell and T-cell ALL.
• This approach demonstrates potential for selective elimination of ALL cells while preserving normal immune populations.
• The targeted approach minimizes on-target toxicity, enhancing therapeutic potential.