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      The Future of Natural Killer Cell Immunotherapy for B Cell Non-Hodgkin Lymphoma (B Cell NHL)

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          Opinion statement

          Natural killer (NK) cells have played a critical—if largely unrecognized or ignored—role in the treatment of B cell non-Hodgkin lymphoma (NHL) since the introduction of CD20-directed immunotherapy with rituximab as a cornerstone of therapy over 25 years ago. Engagement with NK cells leading to lysis of NHL targets through antibody-dependent cellular cytotoxicity (ADCC) is a critical component of rituximab’s mechanism of action. Despite this important role, the only aspect of B cell NHL therapy that has been adopted as standard therapy that even indirectly augments or restores NK cell function is the introduction of obinutuzumab, a CD20 antibody with enhanced ability to engage with NK cells. However, over the last 5 years, adoptive immunotherapy with effector lymphocytes of B cell NHL has experienced tremendous growth, with five different CAR T cell products now licensed by the FDA, four of which target CD19 and have approved indications for some subtype of B cell NHL—axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, and tisagenlecleucel. These T cell-based immunotherapies essentially mimic the recognition, activation pathway, and cytotoxic machinery of a CD19 antibody engaging NK cells and lymphoma targets. Despite their efficacy, these T cell-based immunotherapies have been difficult to implement because they require 4–6 weeks of manufacture, are costly, and have significant toxicities. This renewed interest in the potential of cellular immunity—and the manufacturing, supply chain, and administration logistics that have been addressed with these new agents—have ignited a new wave of enthusiasm for NK cell-directed therapies in NHL. With high safety profiles and proven anti-lymphoma efficacy, one or more new NK cell-directed modalities are certain to be introduced into the standard toolbox of NHL therapy within the next few years, be it function-enhancing cytokine muteins, multi-domain NK cell engagers, or adoptive therapy with expanded or genetically modified NK cells.

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          Most cited references102

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          Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

          Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
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            Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

            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 .)
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              Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial

              Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.
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                Author and article information

                Contributors
                Yaya_Chu@NYMC.edu
                Margaret.Lamb2@nationwidechildrens.org
                Mitchell_Cairo@NYMC.EDU
                dean.lee@nationwidechildrens.org
                Journal
                Curr Treat Options Oncol
                Curr Treat Options Oncol
                Current Treatment Options in Oncology
                Springer US (New York )
                1527-2729
                1534-6277
                8 March 2022
                8 March 2022
                2022
                : 23
                : 3
                : 381-403
                Affiliations
                [1 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Department of Pediatrics, , New York Medical College, ; Valhalla, NY USA
                [2 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, Hematology, Oncology, and Blood and Marrow Transplant Section, , Nationwide Children’s Hospital, ; Columbus, OH USA
                [3 ]GRID grid.261331.4, ISNI 0000 0001 2285 7943, Department of Pediatrics, College of Medicine, , The Ohio State University, ; Columbus, OH USA
                [4 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Department of Medicine, , New York Medical College, ; Valhalla, NY USA
                [5 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Department of Pathology, , New York Medical College, ; Valhalla, NY USA
                [6 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Department of Microbiology and Immunology, , New York Medical College, ; Valhalla, NY USA
                [7 ]GRID grid.260917.b, ISNI 0000 0001 0728 151X, Department of Cell Biology and Anatomy, , New York Medical College, ; Valhalla, NY USA
                [8 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, Center for Childhood Cancer and Blood Disorders, , Abigail Wexner Research Institute at Nationwide Children’s Hospital, ; Columbus, OH USA
                Article
                932
                10.1007/s11864-021-00932-2
                8930876
                35258793
                756460c7-2603-4057-bf4a-cd5943d2b98d
                © The Author(s) 2022

                Open Access This 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/.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: U54 CA232561
                Award ID: U54 CA232561
                Funded by: FundRef http://dx.doi.org/10.13039/100003287, Rally Foundation;
                Award ID: N/A
                Funded by: FundRef http://dx.doi.org/10.13039/100000902, Pediatric Cancer Research Foundation;
                Award ID: N/A
                Funded by: Children's Cancer Fund
                Award ID: N/A
                Categories
                Lymphoma (JL Muñoz, Section Editor)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2022

                Oncology & Radiotherapy
                nk cells,antibody-dependent direct cytotoxicity,non-hodgkin lymphoma,chimeric antigen receptor

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