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      Cytokine release syndrome

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          Abstract

          During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

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          Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

          Catherine Lindgren, Assaf P. Oron, Daniel Li … (2017)
          Publisher's Note: There is an [Related article:] Inside Blood Commentary on this article in this issue. Defined-composition manufacturing platform of CD19 CAR T cells contributes to >90% intent-to-treat complete remission rate. Uniformity of durable persistence of CAR T cells and mitigation of antigen escape are key aspects for further optimization. Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 10 6 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD − ) remission rate for this phase 1 study was 89%. The MRD − remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.
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            Therapeutic T cell engineering

            Michel Sadelain, Isabelle Rivière, Stanley Riddell (2017)
            Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered
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              Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia.

              Arend von Stackelberg, Franco Locatelli, Gerhard Zugmaier … (2016)
              Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m(2)/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m(2)/d for the first 7 days, followed by 15 µg/m(2)/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.
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                Author and article information

                Contributors
                Alexander Shimabukuro-Vornhagen:
                ORCID: http://orcid.org/0000-0002-2351-7294
                shima@uk-koeln.de
                Journal
                Journal ID (nlm-ta): J Immunother Cancer
                Journal ID (iso-abbrev): J Immunother Cancer
                Title: Journal for Immunotherapy of Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2051-1426
                Publication date (Electronic): 15 June 2018
                Publication date PMC-release: 15 June 2018
                Publication date Collection: 2018
                Volume: 6
                Electronic Location Identifier: 56
                Affiliations
                [1 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Cologne Interventional Immunology, , University Hospital of Cologne, ; Cologne, Germany
                [2 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Intensive Care Program, Department I of Internal Medicine, , University Hospital of Cologne, ; Cologne, Germany
                [3 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Center of Integrated Oncology Cologne-Bonn, , University Hospital of Cologne, ; Cologne, Germany
                [4 ]Intensive Care in Hemato-Oncologic Patients (iCHOP), Cologne, Germany
                [5 ]Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
                [6 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Translational Cancer Immunology, , Gene Centre, University of Munich, ; Munich, Germany
                [7 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), ; Heidelberg, Germany
                [8 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Department of General, Visceral and Cancer Surgery, , University Hospital of Cologne, ; Cologne, Germany
                [9 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, Department of Dermatology/Venereology, , University Hospital of Cologne, ; Cologne, Germany
                [10 ]Comprehensive Cancer Center Munich (CCCM), Munich, Germany
                Author information
                http://orcid.org/0000-0002-2351-7294
                Article
                Publisher ID: 343
                DOI: 10.1186/s40425-018-0343-9
                PMC ID: 6003181
                PubMed ID: 29907163
                SO-VID: 8a77cc32-adbd-4bb8-a5cd-253b98ff3499
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                Date received : 24 November 2017
                Date accepted : 20 April 2018
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                Keywords: cytokine release syndrome,immunotherapy,car t cells,t cell-engaging therapies,cytokine storm
                Data availability:
                Keywords: cytokine release syndrome, immunotherapy, car t cells, t cell-engaging therapies, cytokine storm

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