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      Adoptive cell transfer: new perspective treatment in veterinary oncology

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          Abstract

          Cancer immunotherapy is recently considered the most promising treatment for human patients with advanced tumors and could be effectively combined with conventional therapies such as chemotherapy or radiotherapy. Patients with hematological malignancies and melanoma have benefited greatly from immunotherapies such as, adoptive cell transfer therapy, experiencing durable remissions and prolonged survival. In the face of increasing enthusiasm for immunotherapy, particularly for the administration of tumor-specific T lymphocytes, the question arises whether this method could be employed to improve treatment outcomes for canine patients. It is warranted to determine whether veterinary clinical trials could support comparative oncology research and thus facilitate the development of new cell-based therapies for humans. Herein, we discuss adoptive transfer of T lymphocytes and lymphokine-activated cells for application in veterinary oncology, in the context of human medicine achievements. Furthermore, we discuss potential benefits of using domestic dog as a model for immunotherapy and its advantages for translational medicine. We also focus on an emerging genome-editing technology as a useful tool to improve a T cells’ phenotype.

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          Most cited references71

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          Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.

          An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.
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            Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.

            Lymphocytes extracted from freshly resected melanomas can be expanded in vitro and can often mediate specific lysis of autologous tumor cells but not allogeneic tumor or autologous normal cells. We treated 20 patients with metastatic melanoma by means of adoptive transfer of these tumor-infiltrating lymphocytes and interleukin-2, after the patients had received a single intravenous dose of cyclophosphamide. Objective regression of the cancer was observed in 9 of 15 patients (60 percent) who had not previously been treated with interleukin-2 and in 2 of 5 patients (40 percent) in whom previous therapy with interleukin-2 had failed. Regression of cancer occurred in the lungs, liver, bone, skin, and subcutaneous sites and lasted from 2 to more than 13 months. Toxic effects of interleukin-2 occurred, although the treatment course was short (five days); these side effects were reversible. It appears that in patients with metastatic melanoma, this experimental treatment regimen can produce higher response rates than those achieved with interleukin-2 administered alone or with lymphokine-activated killer cells. It is too early to determine whether this new form of immunotherapy can improve survival, but further trials seem warranted.
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              Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype.

              We demonstrate CRISPR-Cas9-mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ∼1/250 liver cells. Expansion of Fah-positive hepatocytes rescued the body weight loss phenotype. Our study indicates that CRISPR-Cas9-mediated genome editing is possible in adult animals and has potential for correction of human genetic diseases.
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                Author and article information

                Contributors
                jkbujak11@gmail.com
                rafal.pingwara@gmail.com
                nelsonmh@musc.edu
                kinga_majchrzak@sggw.pl
                Journal
                Acta Vet Scand
                Acta Vet. Scand
                Acta Veterinaria Scandinavica
                BioMed Central (London )
                0044-605X
                1751-0147
                11 October 2018
                11 October 2018
                2018
                : 60
                : 60
                Affiliations
                [1 ]ISNI 0000 0001 1955 7966, GRID grid.13276.31, Department of Physiological Sciences, Faculty of Veterinary Medicine, , Warsaw University of Life Sciences, ; ul. Nowoursynowska 159, 02-776 Warsaw, Poland
                [2 ]ISNI 0000 0001 2189 3475, GRID grid.259828.c, Department of Microbiology and Immunology, , Medical University of South Carolina, ; 86 Jonathan Lucas Street HCC-612, Charleston, SC 29425 USA
                Author information
                http://orcid.org/0000-0002-9504-4588
                Article
                414
                10.1186/s13028-018-0414-4
                6180494
                30305130
                b51b14e0-02af-4e09-8c9f-3dbce22fbb00
                © The Author(s) 2018

                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.

                History
                : 17 October 2017
                : 2 October 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki;
                Award ID: UMO-2016/21/N/NZ6/02137
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001870, Fundacja na rzecz Nauki Polskiej;
                Award ID: FIRST TEAM 0107
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Veterinary medicine
                adoptive cell transfer,canine oncology,gene editing,immunotherapy,t lymphocytes

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