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      Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

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          Abstract

          Immune-based therapeutic strategies have drastically changed the landscape of hematological disorders, as they have introduced the concept of boosting immune responses against tumor cells. Anti-CD20 monoclonal antibodies have been the first form of immunotherapy successfully applied in the treatment of CLL, in the context of chemoimmunotherapy regimens. Since then, several immunotherapeutic approaches have been studied in CLL settings, with the aim of exploiting or eliciting anti-tumor immune responses against leukemia cells. Unfortunately, despite initial promising data, results from pilot clinical studies have not shown optimal results in terms of disease control - especially when immunotherapy was used individually - largely due to CLL-related immune dysfunctions hampering the achievement of effective anti-tumor responses. The growing understanding of the complex interactions between immune cells and the tumor cells has paved the way for the development of new combined approaches that rely on the synergism between novel agents and immunotherapy. In this review, we provide an overview of the most successful and promising immunotherapeutic modalities in CLL, including both antibody-based therapy (i.e. monoclonal antibodies, bispecific antibodies, bi- or tri- specific killer engagers) and adoptive cellular therapy (i.e. CAR T cells and NK cells). We also provide examples of successful new combination strategies and some insights on future perspectives.

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          Most cited references116

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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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              PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma

              New England Journal of Medicine, 372(4), 311-319
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                21 February 2022
                2022
                : 12
                : 837531
                Affiliations
                [1] 1 University Division of Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino , Torino, Italy
                [2] 2 Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
                Author notes

                Edited by: Renato Zambello, University of Padua, Italy

                Reviewed by: Massimo Gentile, Health Agency of Cosenza, Italy; Stefano Molica, Azienda Ospedaliera Pugliese Ciaccio, Italy

                *Correspondence: Marta Coscia, marta.coscia@ 123456unito.it

                †These authors have contributed equally to this work and share last authorship

                This article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.837531
                8898826
                35265527
                8e10cf3e-d5fd-4914-bd62-a49365060558
                Copyright © 2022 Perutelli, Jones, Griggio, Vitale and Coscia

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 December 2021
                : 31 January 2022
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 116, Pages: 12, Words: 5799
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                chronic lymphocytic leukemia,immunotherapy,monoclonal antibodies,car t cells,car nk cells

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