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      Ipilimumab for Patients with Relapse after Allogeneic Transplantation.

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          Abstract

          Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect.

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          Most cited references14

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          Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.

          Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Bristol-Myers Squibb. Copyright 2010 Elsevier Ltd. All rights reserved.
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            CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation.

            Relapse of malignancy after allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Blockade of the CTLA4 molecule can effectively augment antitumor immunity mediated by autologous effector T cells. We have assessed the safety and preliminary efficacy of a neutralizing, human anti-CTLA4 monoclonal antibody, ipilimumab, in stimulating the graft-versus-malignancy (GVM) effect after allo-HCT. Twenty-nine patients with malignancies that were recurrent or progressive after allo-HCT, received ipilimumab as a single infusion at dose cohorts between 0.1 and 3.0 mg/kg. Dose-limiting toxicity was not encountered, and ipilimumab did not induce graft-versus-host disease (GVHD) or graft rejection. Organ-specific immune adverse events (IAE) were seen in 4 patients (grade 3 arthritis, grade 2 hyperthyroidism, recurrent grade 4 pneumonitis). Three patients with lymphoid malignancy developed objective disease responses following ipilimumab: complete remission (CR) in 2 patients with Hodgkin disease and partial remission (PR) in a patient with refractory mantle cell lymphoma. At the 3.0 mg/kg dose, active serum concentrations of ipilimumab were maintained for more than 30 days after a single infusion. Ipilimumab, as administered in this clinical trial, does not induce or exacerbate clinical GVHD, but may cause organ-specific IAE and regression of malignancy. This study is registered at (http://clinicaltrials.gov) under NCI protocol ID P6082.
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              Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism.

              Acute graft-vs-host disease (GVHD) is influenced by pathways that can enhance or reduce lethality by providing positive or negative signals to donor T cells. To date, the only reported pathway to inhibit GVHD is the CTLA-4:B7 pathway. Because absence of the programmed death-1 (PD-1) pathway has been implicated in a predisposition to autoimmunity and hence a lack of negative signals, the effect of PD-1 pathway blockade on GVHD was explored using several distinct approaches. In each, GVHD lethality was markedly accelerated. Coblockade of CTLA-4 and PD-1 was additive in augmenting GVHD, indicating that these pathways are not fully redundant. Although neither perforin nor Fas ligand expression was required for GVHD enhancement, donor IFN-gamma production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-gamma production and suggest a novel therapeutic target for inhibiting GVHD lethality.
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                Author and article information

                Journal
                N. Engl. J. Med.
                The New England journal of medicine
                New England Journal of Medicine (NEJM/MMS)
                1533-4406
                0028-4793
                Jul 14 2016
                : 375
                : 2
                Affiliations
                [1 ] From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School (M.S.D., H.T.K., P.B., R.L., A.S., A.P.L., M.H., M.S., F.S.H., C.J.W., V.T.H., C. Cutler, J.K., E.P.A., J.H.A., P.A., J.R., R.J.S.), the Bone Marrow Transplant Program, Beth Israel Deaconess Medical Center and Harvard Medical School (D.A.), the Bone Marrow Transplant Program, Massachusetts General Hospital Cancer Center and Harvard Medical School (Y.-B.C.), the Departments of Dermatology (N.R.L.) and Pathology (S.R.G., J.L.H., S.J.R.), Dana-Farber and Brigham and Women's Cancer Center, and the Dana-Farber Cancer Institute, Center for Molecular Oncologic Pathology (M.B., C.W.Z.) - all in Boston; Broad Institute of Massachusetts Institute of Technology and Harvard (P.B., C.J.W.) and Neon Therapeutics (M.S.R.) - both in Cambridge; the Blood and Marrow Transplant Program, University of California, San Diego, Moores Cancer Center, La Jolla (C. Costello, E.D.B.); Colorado Blood Cancer Institute, Denver (P.M.); Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (H.S.); and the Blood and Marrow Transplant Group of Georgia at Northside Hospital, Atlanta (A.B.).
                Article
                NIHMS809157
                10.1056/NEJMoa1601202
                5149459
                27410923
                d4e26a61-8a09-4b0e-80d7-09fb22cfd19a
                History

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