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. 2021 Jun 5;13(11):2816. doi: 10.3390/cancers13112816

Figure 2.

Figure 2

Schematization of chimeric antigen receptor (CAR) T-cell limitations in acute myeloid leukemia (AML) therapy and possible strategies to overcome them. Cytokine release syndrome (CRS) and neurotoxicity are the most frightening side effects related to the use of CAR T-cells in patients. Strategies to deplete CAR/CAR T-cells (e.g., mRNA electroporation of the CAR, suicide switches, drug-inducible on–off switches, and antibody-mediated depletion) could be employed to reduce the persistence of the toxicity. Due to the absence of an ideal target in AML, CAR T-cells impact normal cells expressing the target antigen. Thus, it is essential to identify suitable neoantigens and novel potential targets (leukemia-specific). To overcome on-target/off-tumor toxicity, AND- and NOT-logic-gated CAR can be employed to increase specificity. Affinity fine-tuning, CAR/CAR T-cell depletion strategies, and a combination of CAR therapies with allogeneic HSPC transplantation edited out for CAR target are further solutions to be considered. Antigen loss can occur upon CAR treatment. However, the targeting of neoantigens, stably expressed on leukemic cells, or of multiple antigens should overcome it. AML inter- and intra-patient heterogeneity renders extremely difficult a general application of CAR T in all AML patients, suggesting that a personalized approach and combinatorial CAR strategies are required. Lastly, AML-BM niche might affect CAR T-cell functionality due to its hypoxic and immunosuppressive nature. Moreover, it could protect LSC from CAR T-cell effectiveness. Strategies to combat immunosuppression should be considered alongside CAR infusion. Armored or switch receptor CAR can be employed as well. Specific antigen expression or hypoxia can be exploited for CAR trafficking or niche targeting increasing CAR T potency in the cradle of LSC. To overcome potential alterations of AML T-cells that can render them not suitable for CAR T-cell manufacturing, allogeneic T-cells engineered to bypass graft-versus-host disease and rejection and to express CAR can be used. CRS, cytokine release syndrome; CAR, chimeric antigen receptor; LSC, leukemic stem cells; AML, acute myeloid leukemia; HSPC; hematopoietic stem and progenitor cells; BM, bone marrow; MDSC, myeloid-derived suppressor cells; Tregs, regulatory T-cells.