The Rise of Fine-Tuned CAR-Based Therapies Against Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy with poor prognosis despite multiple available therapies. While chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell malignancies, its application in AML has been limited by early relapses and severe toxicities. Unlike B-cell antigens, most AML-associated surface antigens are also expressed on healthy hematopoietic stem and progenitor cells, creating significant risks of on-target/off-tumor toxicity and prolonged myeloablation. To address the scarcity of AML-specific targets, several innovative CAR strategies have been developed to enhance precision, safety, and efficacy. Logic-gated CARs improve selectivity through dual-antigen recognition or conditional activation. Drug-inducible and transient expression systems, as well as pharmacologic or suicide switches, enable controlled modulation or elimination of CAR cells to reduce toxicity. Adapter CAR platforms allow real-time, flexible targeting, while engineered modulation of gene expression or cytokine secretion enhances persistence and antitumor activity. Finally, alternative immune cells, including natural killer (NK) cells and macrophages, provide versatile platforms that may overcome limitations of conventional T-cell therapies, such as fratricide or challenges in allogeneic use. This review provides a comprehensive overview of these emerging CAR approaches, highlighting their advantages, limitations, and potential to expand immunotherapeutic strategies for AML.