Harnessing TSC-100: Unleashing the Power of Natural HA-1-specific TCRs in Post-Transplant Leukemia Therapy

A significant portion of AML patients experience relapse after hematopoietic stem cell transplant, necessitating new treatment strategies. Some patients have been observed to develop a beneficial graft-versus-leukemia T cell response against the HA-1 antigen, which is linked to reduced relapse rates. Recognizing the potential of targeting the HA-1 antigen, researchers have developed a high-throughput platform for identifying TCRs from healthy donors.

Using this platform, they screened a vast number of naive CD8+ T cells from several donors and identified numerous HA-1-specific TCRs. They refined the list by testing for expression and the ability to target HA-1+ cells, using a clinical-stage TCR as a benchmark. Modifications to the TCR constant region were explored to enhance expression and pairing, and a lentiviral vector was engineered to facilitate the purification of modified T cells.

The top TCR candidates were then evaluated for their cytotoxicity, cytokine production, and proliferation capabilities against a range of cell lines expressing HA-1. The most promising TCR, TSC-100, was further tested for its reactivity against a variety of HLA types and for off-target effects using a comprehensive T-Scan platform.

TSC-100 demonstrated effectiveness comparable to or exceeding that of the benchmark TCR, particularly against cells with low HA-1 and MHC-I expression. Importantly, it showed minimal allo-reactivity and off-target effects. Based on these findings, TSC-100 is being prepared for first-in-human trials, representing a promising development in TCR immunotherapy for liquid tumors.

The study was conducted with ethical approval, using clinical samples collected under IRB-approved protocols. The results underscore the potential of TCR immunotherapy in targeting minor histocompatibility antigens like HA-1, offering a new avenue for treating relapsed leukemia.