Abstract
Simple SummaryAcute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Allogeneic hematopoietic cell transplantation (allo-HCT) has been the only potentially curative treatment for the majority of patients. The ability of chimeric antigen receptor (CAR)-modified T-cell therapy directed against the CD19 antigen to induce durable remissions in patients with acute lymphoblastic leukemia (ALL) has provided optimism that this novel treatment paradigm can be extrapolated to AML. In this review, we provide an overview of candidate target antigens for CAR-T-cells in AML, an update on recent progress in preclinical and clinical development of investigational CAR-T-cell products, and discuss challenges for the clinical implementation of CAR-T-cell therapy in AML.Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them.
Highlights
Acute myeloid leukemia (AML) is a clonal proliferative neoplasm usually characterized by bone marrow, blood, and other tissue infiltration
Though the patient with the deepest partial remission relapsed, this study provided proof-of-concept and spurred the quest for additional targets and improved chimeric antigen receptor (CAR)-T-cell products in AML
Several groups developed CD123-specific CAR-T-cells and showed efficacy in in vivo models, including against AML blasts with relatively low CD123 expression [51–54]. These promising outcomes are countered by reports of in vitro toxicity screens utilizing colony forming unit assays that demonstrate significantly hindered differentiation of healthy hematopoietic stem cells when co-cultured with CD123-specific CAR-T-cells [51,55]
Summary
Acute myeloid leukemia (AML) is a clonal proliferative neoplasm usually characterized by bone marrow, blood, and other tissue infiltration. The prognosis depends on the molecular and cytogenetic features approved by the 2016 revision of the WHO classification of myeloid neoplasm and acute leukemia [2] and the ELN recommendation [3]. For the last three decades, allogeneic hematopoietic cell transplantation (allo-HCT) has been the first immune-based therapy and only potentially curative approach widely used in intermediate and high-risk AML. Because allo-HCT is restricted to a subset of relatively young patients with a low comorbidity index and good performance status [5–7], new tolerable and effective therapeutic approaches are needed. Over the past two decades, AML and other hematological malignancies have become targets for the developing field of immune therapy, such as antibody-based therapeutics, dendritic cell vaccines, TCR-T-cell therapy, and gene-engineered chimeric antigen receptor (CAR)-T-cells, coupled with conventional chemotherapy and molecular targeted therapy [8–11]. Following the discovery of immune inhibitory mechanisms and cancerrelated antigens on leukemic cells, immune approaches are evolving constantly
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