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      Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome

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          ABSTRACT

          Carcinoembryonic antigen (CEA) is a cell surface antigen highly expressed in various cancer cell types and in healthy tissues. It has the potential to be a target for chimeric antigen receptor (CAR)-modified T-cell therapy; however, the safety of this approach in terms of on-target/off-tumor effects needs to be determined. To address this issue in a clinically relevant model, we used a mouse model in which the T cells expressing CEA-specific CAR were transferred into tumor-bearing CEA-transgenic (Tg) mice that physiologically expressed CEA as a self-antigen. The adoptive transfer in conjunction with lymphodepleting and myeloablative preconditioning mediated significant tumor regression but caused weight loss in CEA-Tg, but not in wild-type mice. The weight loss was not associated with overt inflammation in the CEA-expressing gastrointestinal tract but was associated with malnutrition, reflected in elevated systemic levels of cytokines linked to anorexia, which could be controlled by the administration of an anti-IL-6 receptor monoclonal antibody without compromising efficacy. The apparent relationship between lymphodepleting and myeloablative preconditioning, efficacy, and off-tumor toxicity of CAR-T cells would necessitate the development of CEA-specific CAR-T cells with improved signaling domains that require less stringent preconditioning for their efficacy. Taken together, these results suggest that CEA-specific CAR-based adoptive T-cell therapy may be effective for patients with CEA + solid tumors. Distinguishing the fine line between therapeutic efficacy and off-tumor toxicity would involve further modifications of CAR-T cells and preconditioning regimens.

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          Most cited references32

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          Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes

          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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            T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

            Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74-99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was induced in all three patients. This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen. It also emphasizes the destructive power of small numbers of highly avid T cells and the limitations of using CEA as a target for cancer immunotherapy.
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              Cytokine-induced sickness behaviour: mechanisms and implications.

              Sickness behaviour represents the expression of the adaptive reorganization of the priorities of the host during an infectious episode. This process is triggered by pro-inflammatory cytokines produced by peripheral phagocytic cells in contact with invading micro-organisms. The peripheral immune message is relayed to the brain via a fast neural pathway and a slower humoral pathway, resulting in the expression of pro-inflammatory cytokines in macrophage-like cells and microglia in the brain. The cellular and molecular components of this previously unsuspected system are being progressively identified. These advances are opening new avenues for understanding brain disorders, including depression.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                KONI
                koni20
                Oncoimmunology
                Taylor & Francis
                2162-4011
                2162-402X
                2016
                25 July 2016
                25 July 2016
                : 5
                : 9
                : e1211218
                Affiliations
                [a ]Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine , Tsu, Mie, Japan
                [b ]Faculty of Nursing Science, Suzuka Medical Science University , Suzuka, Mie, Japan
                [c ]Takara Bio, Inc. , Shiga, Japan
                [d ]Department of Pathology, Institute of Medical Science, Medical Research Center, Tokyo Medical University , Tokyo, Japan
                [e ]Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine , Tsu, Mie, Japan
                [f ]Center for Comprehensive Cancer Immunotherapy, Mie University , Tsu, Mie, Japan
                Author notes
                CONTACT Takuma Kato, Ph.D, Email: katotaku@ 123456doc.medic.mie-u.ac.jp , Center for Comprehensive Cancer Immunotherapy, Mie University Graduate School of Medicine , 2-174 Edobashi, Tsu, Mie 514-8507, Japan

                Supplemental data for this article can be accessed on the publisher's website.

                Article
                1211218
                10.1080/2162402X.2016.1211218
                5048773
                27757303
                879be5f2-7f07-414d-b62a-3fbc9cb7b5c0
                © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                : 9 February 2016
                : 29 June 2016
                : 3 July 2016
                Page count
                Figures: 6, Tables: 0, References: 52, Pages: 13
                Categories
                Original Research

                Immunology
                adoptive t-cell therapy,carcinoembryonic antigen,chimeric antigen receptor,cytokine release syndrome,neurotoxicity,preconditioning

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