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      Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT

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      1 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37
      Haematologica
      Ferrata Storti Foundation

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          Abstract

          Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.

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          Most cited references91

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          Inducible apoptosis as a safety switch for adoptive cell therapy.

          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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            Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia

            Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.
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              Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study.

              Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. In a phase I-II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per muL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00423124. From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17-66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34-127) from transplantation and 23 days (13-42) from infusion. Ten patients developed acute GVHD (grade I-IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25-73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. MolMed SpA, Italian Association for Cancer Research.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                haematol
                Haematologica
                Haematologica
                Ferrata Storti Foundation
                0390-6078
                1592-8721
                January 2020
                19 September 2019
                : 105
                : 1
                : 47-58
                Affiliations
                [1 ]Department of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
                [2 ]Department of Haematology and EBMT Paris study office / CEREST-TC, Saint Antoine Hospital, Paris, France
                [3 ]Department of Oncology Hematologic Malignancies, Johns Hopkins University School of Medicine, Baltimore, MD, USA
                [4 ]Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
                [5 ]Department of Laboratory Medicine, CAST, Karolinska Institutet and University Hospital, Stockholm, Sweden
                [6 ]Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA
                [7 ]Stem Cell Transplant and Cellular Therapy, Thammasat University, Pathumthani, Thailand
                [8 ]Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
                [9 ]Peking University People’s Hospital, Peking University Institute of Hematology, Beijing China
                [10 ]Department of Pediatric Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Sapienza, University of Rome, Italy
                [11 ]Department of Medicine and Surgery, University of Parma, Parma, Italy
                [12 ]Instituto Clinico Humanitas, Rozzano Milano, Italy
                [13 ]Fondazione Policlinico Universitario Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
                [14 ]University of Perugia, Sant’Andrea Delle Fratte, Perugia Italy
                [15 ]Department of Hematology, Institut Paoli Calmettes, Marseille France
                [16 ]Department of Clinical Psychology, Paoli-Calmettes Institute, Marseille, France
                [17 ]Institut Paoli-Calmette, département de psychologie clinique, Marseille, France
                [18 ]Department of Hematology and Oncology, University Children’s Hospital Tübingen, Tübingen Germany
                [19 ]Division of Hematology and Medical Oncology, Hospital Maisonneuve-Rosemont, Montreal, QC, Canada
                [20 ]Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
                [21 ]Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
                [22 ]Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
                [23 ]Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
                [24 ]HGU Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
                [25 ]Oncology and immunology, Dmitriy Rogachev National Medical Center of pediatric hematology, Moscow, Russia
                [26 ]Adult Hematologic Malignancies & Stem Cell Transplant Section, University Hospitals Seidman Cancer Center, Cleveland, OH, USA
                [27 ]Division of hematology/oncology, University of Virginia Health System, Charlottesville, VA, USA
                [28 ]Dept. of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie Institute - Oncology Center, Gliwice Branch, Gliwice, Poland
                [29 ]Laboratory of Hematology, University of Liège, Liège, Belgium
                [30 ]Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano Italy
                [31 ]Hematology department, Hospital Clínic de Barcelona, Barcelona Spain
                [32 ]Service d’hématologie et thérapie cellulaire Centre international greffes APHP-EBMT-INCa Hospital, Saint Antoine Hospital, Paris France
                [33 ]Bone Marrow Transplantation Unit and CBMDP Donor Center, University Hospital of Patras, Patras, Greece
                [34 ]Department of Hematology and Oncology, Klinikum Augsburg, Augsburg, Germany
                [35 ]Stem Cell Transplant and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
                [36 ]Chaim Sheba Medical Center, Tel Aviv University, Tel-Hashomer, Israel and EBMT ALWP office, Saint Antoine Hospital, Paris, France
                [37 ]Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorobonne University, and INSERM UMRs 938, Paris, France
                Author notes
                Correspondence: BHAGIRATHBHAI DHOLARIA bhagirathbhai.r.dholaria@ 123456vumc.org
                Article
                1050047
                10.3324/haematol.2019.219790
                6939532
                31537691
                3bf7b0f1-09a8-4a5a-b82a-c1e4bdbc7c36
                Copyright© 2020 Ferrata Storti Foundation

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

                History
                : 17 February 2019
                : 19 September 2019
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