The Black Hole: CAR T Cell Therapy in AML

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.

Automated summary

Despite limited progress in adoptive cellular therapies for relapsed/refractory AML compared to B cell malignancies, CAR T cell Phase I trials targeting single antigens have been established worldwide with around 100 patients recruited. The high heterogeneity in AML patients at genetic and molecular levels poses unique therapeutic challenges. This review discusses the need for new perspectives and presents promising novel strategies, including advanced CAR T, TCR-T, and CAR NK therapies, tailored microenvironment and neoantigen targeting, as well as allogeneic approaches.