Emerging strategies in CAR-T cell therapy for acute myeloid leukemia: overcoming heterogeneity and improving safety through dual-antigen targeting

Abstract While CAR-T cell therapy has been very successful for treating B cell malignancies, and more recently multiple myeloma, achieving clinical success for acute myeloid leukemia (AML) remains a significant challenge. The examination of current single-antigen targeting CAR-T cell studies for AML illustrates the challenges faced by this therapy: efficacy limitations arise from the heterogeneity of the disease, which often results in antigen escape and subsequent circumvention of single-antigen targeting CAR-T cells, while safety limitations are mainly due to undesired hematological toxicity stemming from the absence of an antigen specifically expressed on AML tumor cells and not on normal hematopoietic cells. This study offers a comprehensive analysis of the most relevant AML surface antigenic markers —CD123, CD33, ADGRE2, CLL-1, TIM-3, CD70, among others— along with their expression patterns across key cell types, including leukemic blasts, leukemic stem cells, hematopoietic stem cells and progenitors, adult blood cells, and other tissues. Additionally, a variety of strategies for developing CAR-T therapies with improved efficacy and specificity are explored, with dual-antigen targeting CAR-T cell therapies emerging as the most promising approach to overcome the major hurdles observed in single-antigen targeting CAR-T cell therapies. Overall, this review identifies dual-antigen targeting as a therapy holding great prospects in the search of an effective and safe therapeutic approach for AML patients.