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      Chimeric Antigen Receptor (CAR) T Cell Therapy in Acute Myeloid Leukemia (AML)

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          Abstract

          Despite high response rates after initial chemotherapy in patients with acute myeloid leukemia (AML), relapses occur frequently, resulting in a five-year-survival by <30% of the patients. Hitherto, allogeneic hemotopoietic stem cell transplantation (allo-HSCT) is the best curative treatment option in intermediate and high risk AML. It is the proof-of-concept for T cell-based immunotherapies in AML based on the graft-versus-leukemia (GvL)-effect, but it also bears the risk of graft-versus-host disease. CD19-targeting therapies employing chimeric antigen receptor (CAR) T cells are a breakthrough in cancer therapy. A similar approach for myeloid malignancies is highly desirable. This article gives an overview on the state-of-the art of preclinical and clinical studies on suitable target antigens for CAR T cell therapy in AML patients.

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          Inducible apoptosis as a safety switch for adoptive cell therapy.

          Antonio Di Stasi, Siok-Keen Tey, Gianpietro Dotti … (2011)
          Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
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            T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells.

            Eugenia Zah, Meng-Yin Lin, Anne Silva-Benedict … (2016)
            The adoptive transfer of T cells expressing anti-CD19 chimeric antigen receptors (CARs) has shown remarkable curative potential against advanced B-cell malignancies, but multiple trials have also reported patient relapses due to the emergence of CD19-negative leukemic cells. Here, we report the design and optimization of single-chain, bispecific CARs that trigger robust cytotoxicity against target cells expressing either CD19 or CD20, two clinically validated targets for B-cell malignancies. We determined the structural parameters required for efficient dual-antigen recognition, and we demonstrate that optimized bispecific CARs can control both wild-type B-cell lymphoma and CD19(-) mutants with equal efficiency in vivo To our knowledge, this is the first bispecific CAR capable of preventing antigen escape by performing true OR-gate signal computation on a clinically relevant pair of tumor-associated antigens. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity. Cancer Immunol Res; 4(6); 498-508. ©2016 AACRSee related Spotlight by Sadelain, p. 473.
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              Design and development of therapies using chimeric antigen receptor-expressing T cells.

              Gianpietro Dotti, Stephen Gottschalk, Barbara Savoldo … (2014)
              Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR-T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 06 February 2019
                Publication date Collection: February 2019
                Volume: 8
                Issue: 2
                Electronic Location Identifier: 200
                Affiliations
                [1 ]Department of Internal Medicine V (Hematology/Oncology/Rheumatology), University Hospital Heidelberg, 69120 Heidelberg, Germany; Maria-Luisa.Schubert@ 123456med.uni-heidelberg.de (M.-L.S.); Lei.Wang@ 123456med.uni-heidelberg.de (L.W.); hebailin1990@ 123456gmail.com (B.H.); Brigitte.Neuber@ 123456med.uni-heidelberg.de (B.N.); Peter.Dreger@ 123456med.uni-heidelberg.de (P.D.); Carsten.Mueller-Tidow@ 123456med.uni-heidelberg.de (C.M.-T.) Michael.Schmitt@ 123456med.uni-heidelberg.de (M.S.)
                [2 ]National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
                Author notes
                [* ]Correspondence: susanne.hofmann@ 123456med.uni-heidelberg.de ; Tel.: +49-6221-56-6614
                Article
                Publisher ID: jcm-08-00200
                DOI: 10.3390/jcm8020200
                PMC ID: 6406805
                PubMed ID: 30736352
                SO-VID: 95d088a1-18a5-4145-a989-1941bf1e4c2c
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 09 January 2019
                Date accepted : 03 February 2019
                Categories
                Subject: Review

                Keywords: aml,car t cell,immunotherapy
                Data availability:
                Keywords: aml, car t cell, immunotherapy

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