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      Switching on the green light for chimeric antigen receptor T‐cell therapy

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          Abstract

          Adoptive cellular therapy involving genetic modification of T cells with chimeric antigen receptor ( CAR) transgene offers a promising strategy to broaden the efficacy of this approach for the effective treatment of cancer. Although remarkable antitumor responses have been observed following CAR T‐cell therapy in a subset of B‐cell malignancies, this has yet to be extended in the context of solid cancers. A number of promising strategies involving reprogramming the tumor microenvironment, increasing the specificity and safety of gene‐modified T cells and harnessing the endogenous immune response have been tested in preclinical models that may have a significant impact in patients with solid cancers. This review will discuss these exciting new developments and the challenges that must be overcome to deliver a more sustained and potent therapeutic response.

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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.).
          Article 0 comments Cited 495 times – based on 0 reviews     Review now
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            Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

            Helena Harlin, Yuru Meng, Amy C Peterson … (2009)
            Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.
            Article 0 comments Cited 480 times – based on 0 reviews     Review now
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              Coinhibitory Pathways in Immunotherapy for Cancer.

              Susanne H C Baumeister, Gordon J. Freeman, Glenn Dranoff … (2016)
              The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
              Article 0 comments Cited 415 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Paul Andrew Beavis: paul.beavis@petermac.org
                Phillip Kevin Darcy: phil.darcy@petermac.org
                Journal
                Journal ID (nlm-ta): Clin Transl Immunology
                Journal ID (iso-abbrev): Clin Transl Immunology
                Journal ID (doi): 10.1002/(ISSN)2050-0068
                Journal ID (publisher-id): CTI2
                Title: Clinical & Translational Immunology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2050-0068
                Publication date (Electronic): 05 May 2019
                Publication date Collection: 2019
                Volume: 8
                Issue: 5 ( doiID: 10.1002/cti2.2019.8.issue-5 )
                Electronic Location Identifier: e1046
                Affiliations
                [ 1 ] Cancer Immunology Program Peter MacCallum Cancer Centre Melbourne VIC Australia
                [ 2 ] Sir Peter MacCallum Department of Oncology The University of Melbourne Parkville VIC Australia
                [ 3 ] Department of Pathology University of Melbourne Parkville VIC Australia
                [ 4 ] Department of Immunology Monash University Clayton VIC Australia
                Author notes
                [*] [* ] Correspondence

                PA Beavis or PK Darcy, Cancer Immunology Program, Peter MacCallum Cancer Centre, VIC 3000, Australia.

                E‐mails: paul.beavis@ 123456petermac.org ; phil.darcy@ 123456petermac.org

                [†]

                Equal contributors.

                [‡]

                These authors share senior authorship.

                Article
                Publisher ID: CTI21046
                DOI: 10.1002/cti2.1046
                PMC ID: 6500780
                PubMed ID: 31073403
                SO-VID: 6de4c3d2-8ddb-4f35-a21b-f808fce6c3e7
                Copyright © © 2019 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 09 January 2019
                Date revision received : 13 March 2019
                Date accepted : 14 March 2019
                Page count
                Figures: 2, Tables: 0, Pages: 16, Words: 11201
                Funding
                Funded by: National Health and Medical Research Council
                Award ID: APP1062580
                Award ID: APP1132373
                Funded by: Cancer Council of Victoria
                Award ID: APP1143517
                Funded by: National Breast Cancer Foundation Fellowship
                Award ID: ECF‐17‐005
                Funded by: NHMRC Senior Research Fellowship
                Award ID: APP1136680
                Categories
                Subject: Special Feature Review
                Subject: Special Feature Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id cti21046
                cover-date 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:05.05.2019

                Keywords: car,adoptive cell therapy,solid tumors,t cells
                Data availability:
                Keywords: car, adoptive cell therapy, solid tumors, t cells

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