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Review
. 2021 Dec 7;13(24):6157.
doi: 10.3390/cancers13246157.

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia

Marius Maucher  1 , Micha Srour  2 , Sophia Danhof  1 , Hermann Einsele  1 , Michael Hudecek  1 , Ibrahim Yakoub-Agha  3
Affiliations
Review

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia

Marius Maucher et al. Cancers (Basel). .

Abstract

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.

Keywords: AML; CAR-T-cell; adoptive cell therapy; gene therapy; hematology.

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Conflict of interest statement

M.M., M.S. and S.D. declare no conflict of interest. M.H. is listed as a coinventor on patent application related to CAR target antigens and CAR technologies that have been filed by the University of Würzburg, Germany and that have been licensed, in part, to industry. M.H. is a co-founder and equity owner of T-CURX GmbH, Würzburg, Germany; I.Y.-A. has received honoraria from Kite/Gilead, Novartis, Celgene/BMS and Janssen, the companies that are involved in commercial CAR-T-cells. H.E. declares research support/funding: Janssen, BMS/Celgene, Amgen, Sanofi, GSK; consultant work for Janssen, BMS/Celgene, Amgen, Novartis, Takeda; work on scientific advisory boards for Janssen, BMS/Celgene, Amgen, Novartis, Takeda, Sanofi, GSK; honoraria from Janssen, BMS/Celgene, Amgen, Novartis, Takeda, Sanofi, GSK.

Figures

Figure 1
Figure 1
Selection of investigated surface antigen molecules for CAR-T-cell therapy in AML. Depicted membrane proteins on AML blasts or LSCs are recognized by their matching chimeric antigen receptors on gene-engineered T-cells. Abbreviations: CD123: the alpha subunit of the interleukin IL-3 receptor; CD70: the physiological ligand of CD27; CD33: a member of sialic acid-binding immunoglobulin-like lectins (Siglecs); Siglec-6: a member of CD33 (Siglec-3)-related protein superfamily; FLT3: FMS-like tyrosine kinase 3; CLL-1: C-type lectin like molecule-1; CD44v6: a ubiquitous glycoprotein that enables cell adhesion and cell-cell contacts.
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