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      Mesothelin as a biomarker for targeted therapy

      review-article

      1 , 2 , 3 , , 1 , 2

      Biomarker Research

      BioMed Central

      Mesothelin, Biomarker, Targeted therapy, Immunotherapy, CAR-T

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          Abstract

          CAR-T cell therapy targeting CD19 has achieved remarkable success in the treatment of B cell malignancies, while various solid malignancies are still refractory for lack of suitable target. In recent years, a large number of studies have sought to find suitable targets with low “on target, off tumor” concern for the treatment of solid tumors. Mesothelin (MSLN), a tumor-associated antigen broadly overexpressed on various malignant tumor cells, while its expression is generally limited to normal mesothelial cells, is an attractive candidate for targeted therapy. Strategies targeting MSLN, including antibody-based drugs, vaccines and CAR-T therapies, have been assessed in a large number of preclinical investigations and clinical trials. In particular, the development of CAR-T therapy has shown great promise as a treatment for various types of cancers. The safety, efficacy, doses, and pharmacokinetics of relevant strategies have been evaluated in many clinical trials. This review is intended to provide a brief overview of the characteristics of mesothelin and the development of strategies targeting MSLN for solid tumors. Further, we discussed the challenges and proposed potential strategies to improve the efficacy of MSLN targeted immunotherapy.

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          Most cited references 98

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          Inducible apoptosis as a safety switch for adoptive cell therapy.

          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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            Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

            Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
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              Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies.

              Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB co-stimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was demonstrated in both patients and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel anti-self antibodies. These data demonstrate the potential of utilizing mRNA engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope-spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors.
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                Author and article information

                Contributors
                li_peng@gibh.ac.cn
                Journal
                Biomark Res
                Biomark Res
                Biomarker Research
                BioMed Central (London )
                2050-7771
                23 August 2019
                23 August 2019
                2019
                : 7
                Affiliations
                [1 ]ISNI 0000 0004 1798 2725, GRID grid.428926.3, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, ; Guangzhou, China
                [2 ]ISNI 0000 0004 1798 2725, GRID grid.428926.3, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, , Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, ; Guangzhou, China
                [3 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; Shijingshan District, Beijing, China
                Article
                169
                10.1186/s40364-019-0169-8
                6708176
                © The Author(s). 2019

                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.

                Funding
                Funded by: Guangzhou science and technology plan project
                Award ID: 201907010042, 201904010473
                Award Recipient :
                Funded by: The National Major Scientific and Technological Special Project for “Significant New Drugs Development”
                Award ID: SQ2018ZX090201
                Award Recipient :
                Funded by: The Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDB19030205, XDA12050305
                Award Recipient :
                Funded by: Guangdong Provincial Applied Science and Technology Research & Development Program
                Award ID: 2016B020237006
                Award Recipient :
                Funded by: Guangdong Special Support Program
                Award ID: 2017TX04R102
                Award Recipient :
                Funded by: Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province
                Award ID: 2015B020227003
                Award Recipient :
                Funded by: Natural Science Fund of Guangdong Province: Distinguished Young Scholars
                Award ID: 2014A030306028
                Award Recipient :
                Funded by: Natural Science Fund of Guangdong Province: Doctoral Foundation
                Award ID: 2017A030310381
                Award Recipient :
                Funded by: National Natural Science Foundation of China (NSFC)
                Award ID: 81773301; 81700156; 81870121; 81873847
                Award Recipient :
                Funded by: Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory
                Award ID: 2018GZR110105003
                Award Recipient :
                Funded by: Science and Technology Planning Project of Guangdong Province, China
                Award ID: 2017B030314056
                Award Recipient :
                Funded by: Guangzhou Medical University High-level University Construction Research Startup Fund
                Award ID: B195002004013
                Award Recipient :
                Funded by: Research Program of Hefei Institute of Stem Cell and Regenerative Medicine
                Award ID: 2019YF001
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                mesothelin, biomarker, targeted therapy, immunotherapy, car-t

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