Chimeric antigen receptor (CAR)-T cell immunotherapies have revolutionized the treatment of B cell malignancies, in contrast to T cell acute lymphoblastic leukemia (T-ALL) where they are still lacking. The main obstacle to the development of CAR-T therapies in T-ALL is the shared expression of target antigens between leukemic and healthy T cells, leading to CAR-T fratricide and life-threatening T cell aplasia.

We previously developed a CD1a-directed CAR-T strategy for the treatment of cortical T-ALL, a major subtype amounting to ~40% of all de novo T-ALL cases and ~10% of all the relapse/refractory T-ALL cases, that circumvents these limitations and is now on a phase I clinical trial (NCT05679895). 

Here, we report a new CAR-T immunotherapy of T-ALL against a novel target antigen. We validated our antigen’s specificity and safety profile in a large cohort of healthy and leukemic primary samples. We generated a proprietary IgG hybridoma and cloned the humanized sequence of the antigen-binding fragment into a CAR backbone. Our transduced CAR-T cells efficiently and specifically eliminated target cells in both in vitro and in vivo models. Finally, we propose an innovative dual bi-specific immunotherapy, along with CD1a, to cover and treat over 70% of all T-ALL patients.