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      Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future

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          Abstract

          The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In the last 3 decades, NK cells have been utilized to harness the anti-tumor immune response in a wide range of malignancies, most notably with early evidence of efficacy in hematologic malignancies. NK cells are dysfunctional in patients with hematologic malignancies, and their number and function are further impaired by chemotherapy, radiation, and immunosuppressants used in initial therapy and hematopoietic stem cell transplantation. Restoring this innate immune deficit may lead to improved therapeutic outcomes. NK cell adoptive transfer has proven to be a safe in these settings, even in the setting of HLA mismatch, and a deeper understanding of NK cell biology and optimized expansion techniques have improved scalability and therapeutic efficacy. Here, we review the use of NK cell therapy in hematologic malignancies and discuss strategies to further improve the efficacy of NK cells against these diseases.

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          Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

          Enli Liu, David Marin, Pinaki B. Banerjee … (2020)
          Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin’s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×10 5 , 1×10 6 , or 1×10 7 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter’s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339 .)
          Article 0 comments Cited 793 times – based on 0 reviews     Review now
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            The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy

            Barbara Muz, Pilar de la Puente, Feda Azab … (2015)
            Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFĸB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.
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              Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity

              Qing Jie Zhang, Jiacheng Bi, Xiaodong Zheng … (2018)
              Article 0 comments Cited 387 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Margaret G. Lamb:
                ORCID: http://orcid.org/0000-0001-9413-3637
                Margaret.lamb2@nationwidechildrens.org
                Journal
                Journal ID (nlm-ta): Stem Cell Res Ther
                Journal ID (iso-abbrev): Stem Cell Res Ther
                Title: Stem Cell Research & Therapy
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1757-6512
                Publication date (Electronic): 25 March 2021
                Publication date PMC-release: 25 March 2021
                Publication date Collection: 2021
                Volume: 12
                Electronic Location Identifier: 211
                Affiliations
                [1 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, Division of Hematology, Oncology, and Bone Marrow Transplant, , Nationwide Children’s Hospital, ; 700 Children’s Drive, Suite 5A.1, Columbus, OH 43205-2664 USA
                [2 ]GRID grid.261331.4, ISNI 0000 0001 2285 7943, Department of Pediatrics, , The Ohio State University School of Medicine, ; Columbus, OH USA
                Author information
                http://orcid.org/0000-0001-9413-3637
                Article
                Publisher ID: 2277
                DOI: 10.1186/s13287-021-02277-x
                PMC ID: 7992329
                PubMed ID: 33397467
                SO-VID: 40763787-b673-4c89-ab01-28510c5cd250
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 5 January 2021
                Date accepted : 10 March 2021
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Molecular medicine
                Keywords: natural killer cells,hematologic malignancy,cellular therapy
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: natural killer cells, hematologic malignancy, cellular therapy

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