Base edited “universal” donor CAR T cell strategies for acute myeloid leukaemia

Acute myeloid leukaemia (AML) is often aggressive and life-threatening with limited curative options. Immunotherapies including chimeric antigen receptor (CAR) T cell approaches are under investigation, but high levels of disease heterogeneity remain a major hurdle to achieving durable responses. Targeting of multiple surface antigens may ensure complete immunological coverage of leukemic blast populations, but such antigens are often also present on healthy haematopoietic populations. To address likely aplasia, strategies can be designed to bridge CAR T cell therapies to allogeneic stem cell transplantation (allo-SCT), as demonstrated in recent anti-CD7 CAR T cell studies. Here we report that monotherapy using base edited (BE) ‘universal’ donor CAR T cells against CD33, CLL-1, or CD7 delivered inhibition of AML in immunodeficient mice when antigen expression was homogenous, but combined use of BE-CAR33 and BE-CARCLL-1 T cells was required to address heterogenous CLL-1 ^-/+ CD33 ^-/+ disease. We also demonstrate that removal of shared CD7 antigens enabled compatibility of BE-CAR33 with BE-CAR7 T cells, including in a patient-derived xenograft (PDX) model of AML. Therapeutic strategies envisage ‘pick and mix’ applications of base edited universal CAR T cells in combinations determined by patient-specific antigen profiles. Such approaches also offer the possibility of deep, cell-based, de-bulking and preparative conditioning ahead of allo-SCT followed by donor-derived reconstitution.