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      Cytokine Release Syndrome: Current Perspectives

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          Abstract

          Chimeric antigen receptor T cell (CART) therapy represents a novel and a paradigm-shifting approach to treating cancer. Recent clinical successes have widened the applicability of CD19 CART cells for the treatment of relapsed/refractory B-cell NHL, namely tisagenleclucel and axicabtagene ciloleucel. Tisagenleclucel is also approved for relapsed and/or refractory B-ALL up to age 25. CART therapy is associated with unique and potentially life-threatening toxicities, notably cytokine release syndrome (CRS). A better understanding of the pathogenesis of CRS is crucial to ensure proper management. In this review, CRS definitions, profiles, risk factors and grading systems are discussed. Finally, current and novel investigational approaches and therapies for CRS are summarized.

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          Most cited references35

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          CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

          Terry Fry, Nirali Shah, Rimas Orentas … (2017)
          Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)
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            Inducible apoptosis as a safety switch for adoptive cell therapy.

            Antonio Di Stasi, Siok-Keen Tey, Gianpietro Dotti … (2011)
            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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              Design and development of therapies using chimeric antigen receptor-expressing T cells.

              Gianpietro Dotti, Stephen Gottschalk, Barbara Savoldo … (2014)
              Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR-T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Immunotargets Ther
                Journal ID (iso-abbrev): Immunotargets Ther
                Journal ID (publisher-id): ITT
                Journal ID (pmc): itt
                Title: ImmunoTargets and Therapy
                Publisher: Dove
                ISSN (Electronic): 2253-1556
                Publication date (Electronic): 29 October 2019
                Publication date Collection: 2019
                Volume: 8
                Pages: 43-52
                Affiliations
                [1 ]Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic , Jacksonville, FL, USA
                [2 ]Department of Malignant Hematology, Moffitt Cancer Center , Tampa, FL, USA
                Author notes
                Correspondence: Mohamed A Kharfan-Dabaja Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic , 4500 San Pablo Road, Mangurian Bdg 3rd Floor, Jacksonville, FL32224, USATel +1 904 953-2000 Email KharfanDabaja.Mohamed@Mayo.Edu
                Author information
                http://orcid.org/0000-0003-4534-4248
                http://orcid.org/0000-0001-7394-5185
                Article
                Publisher ID: 202015
                DOI: 10.2147/ITT.S202015
                PMC ID: 6825470
                PubMed ID: 31754614
                SO-VID: 0f778bab-d8ad-4df0-819d-cae6592a2626
                Copyright © © 2019 Murthy et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 14 August 2019
                Date accepted : 07 October 2019
                Page count
                Tables: 3, References: 74, Pages: 10
                Categories
                Subject: Review

                Keywords: cytokine release syndrome,chimeric antigen receptor t-cell therapy
                Data availability:
                Keywords: cytokine release syndrome, chimeric antigen receptor t-cell therapy

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