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      CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside

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          ABSTRACT

          The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

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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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            Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies.

            Gregory Beatty, Andrew Haas, Marcela Maus … (2014)
            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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              Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes

              Ignazio Caruana, Barbara Savoldo, Valentina Hoyos … (2015)
              Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors 1–3 than in lymphoid malignancies 4, 5 . Although active tumor-mediated immunosuppression may play a role in limiting efficacy 6 , functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cells’ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncoimmunology
                Journal ID (iso-abbrev): Oncoimmunology
                Journal ID (publisher-id): KONI
                Journal ID (publisher-id): koni20
                Title: Oncoimmunology
                Publisher: Taylor & Francis
                ISSN (Print): 2162-4011
                ISSN (Electronic): 2162-402X
                Publication date Collection: 2016
                Publication date (Electronic): 28 October 2016
                Publication date PMC-release: 28 October 2016
                Volume: 5
                Issue: 12
                Electronic Location Identifier: e1251539
                Affiliations
                [a ]Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Science, Tianjin Medical University , Tianjin, China
                [b ]Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Molecular and Cellular Immunology, Tianjin Medical University , Tianjin, China
                [c ]Department of Immunology, Basic Medical College, Weifang Medical University , Weifang, China
                Author notes
                CONTACT Rongxin Zhang rongxinz@ 123456yahoo.com Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Science, Tianjin Medical University , Tianjin 300070, China
                [*]

                These authors contributed equally to this work.

                Article
                Publisher ID: 1251539
                DOI: 10.1080/2162402X.2016.1251539
                PMC ID: 5214859
                PubMed ID: 28123893
                SO-VID: 0d1d9f12-1bf2-439b-916b-5fff211f1ad6
                Copyright © © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                Date received : 26 September 2016
                Date accepted : 17 October 2016
                Page count
                Figures: 1, Tables: 2, References: 104, Pages: 13
                Categories
                Subject: Review

                ScienceOpen disciplines: Immunology
                Keywords: car-t cell; chimeric antigen receptor (car),gastrointestinal cancer,hepatic carcinoma,immunotherapy
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: car-t cell; chimeric antigen receptor (car), gastrointestinal cancer, hepatic carcinoma, immunotherapy

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