The Black Hole: CAR T Cell Therapy in AML Atilla, Erden Benabdellah, Karim Acute myeloid leukemia Cellular therapies Chimeric antigen T cells Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything. One must consider the fact that only around 30% of patients show a response; there are, however, consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single-cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA, and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T, and CAR NK therapies; the approaches with which to tailor the microenvironment and target neoantigens; and allogeneic approaches. 2024-09-23T10:45:45Z 2024-09-23T10:45:45Z 2023-05-11 journal article Atilla, E.; Benabdellah, K. The Black Hole: CAR T Cell Therapy in AML. Cancers 2023, 15, 2713. https://doi.org/10.3390/cancers15102713 https://hdl.handle.net/10481/94888 10.3390/cancers15102713 eng info:eu-repo/grantAgreement/EC/H2020/CA21113 http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI