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      Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis

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          Abstract

          Chimeric antigen receptor (CAR) modified T cells targeted CD19 showed promising clinical outcomes in treatment of B cell malignances such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) and other indolent lymphomas. However, the clinical benefit varies tremendously among different trials. This meta-analysis investigated the efficacy (response rates and survival time) of CD19-CAR T cells in refractory B cell malignances in Phase I clinical trials. We searched publications between 1991 and 2014 from PubMed and Web of Science. Pooled response rates were calculated using random-effects models. Heterogeneity was investigated by subgroup analysis and meta-regression. Fourteen clinical trials including 119 patients were eligible for response rate evaluation, 62 patients in 12 clinical trials were eligible for progression-free survival analysis. The overall pooled response rate of CD19-CAR T cells was 73% (95% confidence interval [CI]: 46-94%). Significant heterogeneity across estimates of response rates was observed ( p < 0.001, I2=88.3%). ALL patients have higher response rate (93%, 95% CI: 65-100%) than CLL (62%, 95% CI: 27-93%) and lymphoma patients (36%, 95% CI: 1-83%). Meta-regression analysis identified lymphodepletion and no IL-2 administrated T cells as two key factors associated with better clinical response. Lymphodepletion and higher infused CAR T cell number were associated with better prognosis. In conclusion, this meta-analysis showed a high clinical response rate of CD19-CAR T cell-based immunotherapy in treatment of refractory B cell malignancies. Lymphodepletion and increasing number of infused CD19-CAR T cells have positive correlations with the clinical efficiency, on the contrary, IL-2 administration to T cells is not recommended.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Drew M Pardoll (2012)
          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
          Article 0 comments Cited 5123 times – based on 0 reviews     Review now
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            Metaprop: a Stata command to perform meta-analysis of binomial data

            Victoria N Nyaga, Marc Arbyn, Marc Aerts (2014)
            Background Meta-analyses have become an essential tool in synthesizing evidence on clinical and epidemiological questions derived from a multitude of similar studies assessing the particular issue. Appropriate and accessible statistical software is needed to produce the summary statistic of interest. Methods Metaprop is a statistical program implemented to perform meta-analyses of proportions in Stata. It builds further on the existing Stata procedure metan which is typically used to pool effects (risk ratios, odds ratios, differences of risks or means) but which is also used to pool proportions. Metaprop implements procedures which are specific to binomial data and allows computation of exact binomial and score test-based confidence intervals. It provides appropriate methods for dealing with proportions close to or at the margins where the normal approximation procedures often break down, by use of the binomial distribution to model the within-study variability or by allowing Freeman-Tukey double arcsine transformation to stabilize the variances. Metaprop was applied on two published meta-analyses: 1) prevalence of HPV-infection in women with a Pap smear showing ASC-US; 2) cure rate after treatment for cervical precancer using cold coagulation. Results The first meta-analysis showed a pooled HPV-prevalence of 43% (95% CI: 38%-48%). In the second meta-analysis, the pooled percentage of cured women was 94% (95% CI: 86%-97%). Conclusion By using metaprop, no studies with 0% or 100% proportions were excluded from the meta-analysis. Furthermore, study specific and pooled confidence intervals always were within admissible values, contrary to the original publication, where metan was used.
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              The microenvironment in mature B-cell malignancies: a target for new treatment strategies.

              Andreas Rosenwald, R Burger, Federico Caligaris-Cappio … (2009)
              Despite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth and drug resistance. Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive novel strategy for treating selected mature B-cell malignancies. Here we summarize the current knowledge about the cellular and molecular interactions between neoplastic B lymphocytes and accessory cells that shape a supportive microenvironment, and the potential therapeutic targets that are emerging, together with the new problems they raise. We discuss clinically relevant aspects and provide an outlook into future biologically oriented therapeutic strategies. We anticipate a paradigm shift in the treatment of selected B-cell malignancies, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role. Such approaches hopefully will help eliminating residual disease, thereby improving our current therapeutic efforts.
              Article 0 comments Cited 135 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 20 October 2015
                Publication date (Electronic): 10 September 2015
                Volume: 6
                Issue: 32
                Pages: 33961-33971
                Affiliations
                1 Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
                2 Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
                3 Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
                4 Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia
                5 Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, United States
                6 Department of Immunology, Harvard Medical School, Boston, Massachusetts United States
                7 Molecular & Immunological/Bio-Therapeutic Department, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, China
                8 Department of Gastroenterology, Pennsylvania Hospital, University of Pennsylvania, Philadelphia, Pennsylvania, United States
                9 Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital to Academy of Military Medical Science, Beijing, China
                10 Engineering Key Laboratory for Cell Therapy of Henan Province, Zhengzhou, Henan, China
                11 School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
                Author notes
                Correspondence to: Yi Zhang, yizhang@ 123456zzu.edu.cn
                Article
                DOI: 10.18632/oncotarget.5582
                PMC ID: 4741817
                PubMed ID: 26376680
                SO-VID: fd585d81-4ccd-4d7c-a8aa-9838f036b4ab
                Copyright © Copyright: © 2015 Zhang 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 : 6 July 2015
                Date accepted : 20 August 2015
                Categories
                Subject: Clinical Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cd19,chimeric antigen receptor,b cell malignancies,meta analysis,efficiency
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cd19, chimeric antigen receptor, b cell malignancies, meta analysis, efficiency

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