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      Realizing Innate Potential: CAR-NK Cell Therapies for Acute Myeloid Leukemia

      review-article
      1 , 1 , 2 , *
      ,
      Cancers
      MDPI
      CAR-NK, acute myeloid leukemia, immunotherapy

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          Abstract

          Simple Summary

          Infusions of T-cells genetically modified to recognize the protein CD19 (CD19 CAR-T cells) have proven a potent form of cancer therapy for certain cancers arising from B-cells. These treatments, while revolutionary, remain expensive to manufacture using a patients’ own cells and can have considerable side effects. There is great interest in improving upon and expanding the reach of these new treatments to other cancer types. Natural killer (NK) cells are an alternative cell population with unique properties which can also be modified to recognize specific proteins (CAR-NK cells). The properties of CAR-NK cells should allow manufacturing from healthy donor cells with rapid availability and potentially fewer side effects. NK cells have an innate ability to target acute myeloid leukemia (AML). In this review article, we consider the potential that CAR-NK cells possess to enhance this effect and offer a new type of immunotherapy for AML.

          Abstract

          Next-generation cellular immunotherapies seek to improve the safety and efficacy of approved CD19 chimeric antigen receptor (CAR) T-cell products or apply their principles across a growing list of targets and diseases. Supported by promising early clinical experiences, CAR modified natural killer (CAR-NK) cell therapies represent a complementary and potentially off-the-shelf, allogeneic solution. While acute myeloid leukemia (AML) represents an intuitive disease in which to investigate CAR based immunotherapies, key biological differences to B-cell malignancies have complicated progress to date. As CAR-T cell trials treating AML are growing in number, several CAR-NK cell approaches are also in development. In this review we explore why CAR-NK cell therapies may be particularly suited to the treatment of AML. First, we examine the established role NK cells play in AML biology and the existing anti-leukemic activity of NK cell adoptive transfer. Next, we appraise potential AML target antigens and consider common and unique challenges posed relative to treating B-cell malignancies. We summarize the current landscape of CAR-NK development in AML, and potential targets to augment CAR-NK cell therapies pharmacologically and through genetic engineering. Finally, we consider the broader landscape of competing immunotherapeutic approaches to AML treatment. In doing so we evaluate the innate potential, status and remaining barriers for CAR-NK based AML immunotherapy.

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          Most cited references207

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          The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

          The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues was last updated in 2008. Since then, there have been numerous advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemias, largely derived from gene expression analysis and next-generation sequencing that can significantly improve the diagnostic criteria as well as the prognostic relevance of entities currently included in the WHO classification and that also suggest new entities that should be added. Therefore, there is a clear need for a revision to the current classification. The revisions to the categories of myeloid neoplasms and acute leukemia will be published in a monograph in 2016 and reflect a consensus of opinion of hematopathologists, hematologists, oncologists, and geneticists. The 2016 edition represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition. The major changes in the classification and their rationale are presented here.
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            Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma

            In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.
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              Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

              In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                29 March 2021
                April 2021
                : 13
                : 7
                : 1568
                Affiliations
                [1 ]Apoptosis Research Center, National University of Ireland Galway, H91 TK33 Galway, Ireland; m.gurney1@ 123456nuigalway.ie
                [2 ]ONK Therapeutics Ltd., H91 V6KV Galway, Ireland
                Author notes
                Author information
                https://orcid.org/0000-0002-6173-7140
                Article
                cancers-13-01568
                10.3390/cancers13071568
                8036691
                33805422
                6f5f79de-dc37-460e-bb61-bda5eedee238
                © 2021 by the authors.

                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
                : 20 February 2021
                : 25 March 2021
                Categories
                Review

                car-nk,acute myeloid leukemia,immunotherapy
                car-nk, acute myeloid leukemia, immunotherapy

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