Transgenic HA-1-Specific CD8⁺ T-Lymphocytes Selectively Target Leukemic Cells

Area of Science:

• Immunology
• Oncology
• Transplantation

Background:

• Allogeneic hematopoietic stem cell transplantation (allo-HSCT) faces challenges with malignant disease relapse.
• Minor histocompatibility antigens (MiHAs) drive graft-versus-leukemia responses, crucial for transplant success.
• The HA-1 antigen is a key target for leukemia immunotherapy due to its restricted expression in hematopoietic tissues and presentation by HLA A*02:01.

Purpose of the Study:

• To discover and characterize T cell receptors (TCRs) specific for the HA-1 minor histocompatibility antigen.
• To evaluate the potential of HA-1-specific T cells for adoptive immunotherapy to prevent or treat leukemia relapse post-transplant.

Main Methods:

• Bioinformatic analysis and reporter T cell lines were used to identify 13 HA-1-specific T cell receptors (TCRs).
• TCR affinities were assessed by measuring reporter cell line responses to HA-1+ cells.
• CD8+ T cells with engineered HA-1-specific TCRs were tested for their ability to lyse leukemia cells from patients.

Main Results:

• Thirteen HA-1-specific TCRs were identified, with measured affinities.
• The identified TCRs demonstrated no cross-reactivity with a panel of donor cells expressing common HLA alleles.
• Engineered CD8+ T cells successfully lysed hematopoietic cells from patients with acute myeloid, T-cell, and B-cell acute lymphocytic leukemia (n=15).
• No cytotoxicity was observed against HA-1-negative or HLA-A*02-negative cells (n=10).

Conclusions:

• The study identified novel HA-1-specific TCRs with potential therapeutic applications.
• HA-1-specific T cell therapy shows promise for complementing allo-HSCT by targeting residual leukemia.
• These findings support HA-1 as a viable target for post-transplant immunotherapy to improve outcomes in leukemia patients.