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      The efficacy of chimeric antigen receptor (CAR) immunotherapy in animal models for solid tumors: A systematic review and meta-analysis

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      Author(s): 1 , 1 , 1 , 2 , *
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      Publication date (Electronic):
      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Background

          Most recently, an emerging theme in the field of tumor immunology predominates: chimeric antigen receptor (CAR) therapy in treating solid tumors. The number of related preclinical trials was surging. However, an evaluation of the effects of preclinical studies remained absent. Hence, a meta-analysis was conducted on the efficacy of CAR in animal models for solid tumors.

          Methods

          The authors searched PubMed/Medline, Embase, and Google scholar up to April 2017. HR for survival was extracted based on the survival curve. The authors used fixed effect models to combine the results of all the trials. Heterogeneity was assessed by I-square statistic. Quality assessment was conducted following the Stroke Therapy Academic Industry Roundtable standard. Publication bias was assessed using Egger's test.

          Results

          Eleven trials were included, including 54 experiments with a total of 362 animals involved. CAR immunotherapy significantly improved the survival of animals (HR: 0.25, 95% CI: 0.13–0.37, P < 0.001). The quality assessment revealed that no study reported whether allocation concealment and blinded outcome assessment were conducted, and only five studies implemented randomization.

          Conclusions

          This meta-analysis indicated that CAR therapy may be a potential clinical strategy in treating solid tumors.

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          Most cited references18

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          Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.

          M Parmar, V. Torri, L. Stewart (1998)
          Meta-analyses aim to provide a full and comprehensive summary of related studies which have addressed a similar question. When the studies involve time to event (survival-type) data the most appropriate statistics to use are the log hazard ratio and its variance. However, these are not always explicitly presented for each study. In this paper a number of methods of extracting estimates of these statistics in a variety of situations are presented. Use of these methods should improve the efficiency and reliability of meta-analyses of the published literature with survival-type endpoints.
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            Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer.

            Somala Mohammed, Sujita Sukumaran, Pradip Bajgain … (2017)
            The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function. Thus, to protect our cells from the immunosuppressive cytokine IL-4, we generated an inverted cytokine receptor in which the IL-4 receptor exodomain was fused to the IL-7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR-PSCA T cells should invert the inhibitory effects of tumor-derived IL-4 and instead promote T cell proliferation. We now demonstrate the suppressed activity of CAR T cells in tumor-milieu conditions and the ability of CAR/ICR T cells to thrive in an IL-4-rich microenvironment, resulting in enhanced antitumor activity. Importantly, CAR/ICR T cells remained both antigen and cytokine dependent. These findings support the benefit of combining the 4/7 ICR with CAR-PSCA to treat pancreatic cancer, a PSCA-expressing tumor characterized by a dense immunosuppressive environment rich in IL-4.
            Article 0 comments Cited 122 times – based on 0 reviews     Review now
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              T cells redirected to EphA2 for the immunotherapy of glioblastoma.

              Swati Naik, Vita Brawley, Nabil Ahmed … (2013)
              Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.
              Article 0 comments Cited 97 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yingcheng Wu:
                ORCID: http://orcid.org/0000-0001-9473-546X
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Ran Xu: Role: Data curation
                Keren Jia: Role: Data curation
                Hui Shi:
                ORCID: http://orcid.org/0000-0001-6446-4160
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Salvatore V Pizzo: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 November 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 11
                Electronic Location Identifier: e0187902
                Affiliations
                [1 ] Medical School of Nantong University, Jiangsu, China
                [2 ] Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
                Duke University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9473-546X
                http://orcid.org/0000-0001-6446-4160
                Article
                Publisher ID: PONE-D-17-17653
                DOI: 10.1371/journal.pone.0187902
                PMC ID: 5687736
                PubMed ID: 29141027
                SO-VID: 025cc33d-830e-4b51-9b48-5007e0df7cd0
                Copyright © © 2017 Wu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 8 May 2017
                Date accepted : 28 October 2017
                Page count
                Figures: 2, Tables: 3, Pages: 11
                Funding
                The authors received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Cancer Immunotherapy
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Immunology
                Subject: Immunotherapy
                Subject: Cancer Immunotherapy
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Immunotherapy
                Subject: Cancer Immunotherapy
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Clinical Immunology
                Subject: Immunotherapy
                Subject: Cancer Immunotherapy
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Model Organisms
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Model Organisms
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Animal Models
                Subject: Mouse Models
                Subject: Research and Analysis Methods
                Subject: Experimental Organism Systems
                Subject: Animal Models
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Research and Analysis Methods
                Subject: Animal Studies
                Subject: Animal Models of Disease
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Lung and Intrathoracic Tumors
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                Data Availability All relevant data are within the paper.

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