{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:57:32Z","timestamp":1785387452388,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Veterinary Sciences"],"abstract":"<jats:p>Adoptive cell therapy (ACT) has been studied in several human and canine cancers with some promising clinical outcomes but not in canine oral malignant melanoma (OMM). Our manuscript aimed to explore one kind of ACT, the ex vivo-expanded autologous immune cell infusion in canine OMM, as this tumor remains a treatment dilemma. The study recruited dogs with histopathological diagnoses of oral malignant melanoma, generated their peripheral blood mononuclear cells, expanded them into predominantly non-B non-T cells via stimulations of IL-15, IL-2, and IL-21, and then re-infused the cells into tumor-bearing dogs. Ten dogs were enrolled; three dogs did not report any adverse events; three had a mildly altered appetite; one had a mildly increased liver index, while the other three developed suspected anaphylaxis at different levels. The median progression-free interval was 49 days. Dogs with progressive disease during treatment had a shorter survival. This pilot study indicates limited efficacy with potential adverse events of this ACT. Most recruited patients were in a later stage and had macroscopic disease, which might affect the treatment efficacy. Further exploration of this cell therapy in an adjuvant setting, with adequate protocol modification and standardization, could still be considered.<\/jats:p>","DOI":"10.3390\/vetsci11040150","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T12:09:40Z","timestamp":1711627780000},"page":"150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Limited Clinical Efficacy with Potential Adverse Events in a Pilot Study of Autologous Adoptive Cell Therapy in Canine Oral Malignant Melanoma"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-8341","authenticated-orcid":false,"given":"Yuan-Yuan","family":"Xia","sequence":"first","affiliation":[{"name":"Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipe 10617, Taiwan"},{"name":"National Taiwan University Veterinary Hospital, College of Bioresources and Agriculture, National Taiwan University, Taipei 10672, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwan-Hwa","family":"Chi","sequence":"additional","affiliation":[{"name":"Graduate Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan"},{"name":"Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-8180","authenticated-orcid":false,"given":"Albert Taiching","family":"Liao","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipe 10617, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4424-730X","authenticated-orcid":false,"given":"Jih-Jong","family":"Lee","sequence":"additional","affiliation":[{"name":"National Taiwan University Veterinary Hospital, College of Bioresources and Agriculture, National Taiwan University, Taipei 10672, Taiwan"},{"name":"Graduate Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,28]]},"reference":[{"key":"ref_1","unstructured":"Vail, D.M., Thamm, D.H., and Liptak, J.M. (2020). Withrow and MacEwen\u2019s Small Animal Clinical Oncology, W.B. Saunders. [6th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18311","DOI":"10.1038\/s41598-020-75533-4","article-title":"A pilot clinical study of the therapeutic antibody against canine PD-1 for advanced spontaneous cancers in dogs","volume":"10","author":"Igase","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2287250","DOI":"10.1080\/19420862.2023.2287250","article-title":"Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors","volume":"15","author":"Yoshimoto","year":"2023","journal-title":"mAbs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41698-021-00147-6","article-title":"PD-L1 immunohistochemistry for canine cancers and clinical benefit of anti-PD-L1 antibody in dogs with pulmonary metastatic oral malignant melanoma","volume":"5","author":"Maekawa","year":"2021","journal-title":"npj Precis. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/vco.12690","article-title":"Difference in outcome between curative intent vs marginal excision as a first treatment in dogs with oral malignant melanoma and the impact of adjuvant CSPG4-DNA electrovaccination: A retrospective study on 155 cases","volume":"19","author":"Giacobino","year":"2021","journal-title":"Vet. Comp. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/vco.12744","article-title":"There and back again: Translating adoptive cell therapy to canine cancer and improving human treatment","volume":"19","author":"Brill","year":"2021","journal-title":"Vet. Comp. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13028-018-0414-4","article-title":"Adoptive cell transfer: New perspective treatment in veterinary oncology","volume":"60","author":"Bujak","year":"2018","journal-title":"Acta Vet. Scand."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1038\/mt.2016.146","article-title":"Feasibility and safety of RNA-transfected CD20-specific chimeric antigen receptor T cells in dogs with spontaneous B cell lymphoma","volume":"24","author":"Panjwani","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"824982","DOI":"10.3389\/fvets.2022.824982","article-title":"Case Report: Clinical and serological hallmarks of cytokine release syndrome in a canine B cell lymphoma patient treated with autologous CAR-T cells","volume":"9","author":"Atherton","year":"2022","journal-title":"Front. Vet. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1056\/NEJM198512053132327","article-title":"Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer","volume":"313","author":"Rosenberg","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1056\/NEJM198812223192527","article-title":"Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report","volume":"319","author":"Rosenberg","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1292\/jvms.70.581","article-title":"Phenotypic analysis and effects of sequential administration of activated canine lymphocytes on healthy beagles","volume":"70","author":"Hoshino","year":"2008","journal-title":"J. Vet. Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.vetimm.2016.06.007","article-title":"Change in peripheral blood lymphocyte count in dogs following adoptive immunotherapy using lymphokine-activated T killer cells combined with palliative tumor resection","volume":"177","author":"Mie","year":"2016","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/srep00249","article-title":"Adoptive T-cell therapy improves treatment of canine non-Hodgkin lymphoma post chemotherapy","volume":"2","author":"Sheppard","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"787373","DOI":"10.3389\/fvets.2021.787373","article-title":"A Retrospective Analysis: Autologous peripheral blood hematopoietic stem cell transplant combined with adoptive T-cell therapy for the treatment of high-grade B-cell lymphoma in ten dogs","volume":"8","author":"Gareau","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1111\/jvim.15852","article-title":"Autologous cancer cell vaccination, adoptive T-cell transfer, and interleukin-2 administration results in long-term survival for companion dogs with osteosarcoma","volume":"34","author":"Flesner","year":"2020","journal-title":"J. Vet. Intern. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41568-022-00491-0","article-title":"Natural killer cells in antitumour adoptive cell immunotherapy","volume":"22","author":"Laskowski","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Oh, S., Lee, J.H., Kwack, K., and Choi, S.W. (2019). Natural killer cell therapy: A new treatment paradigm for solid tumors. Cancers, 11.","DOI":"10.3390\/cancers11101534"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9291","DOI":"10.1002\/jcp.29827","article-title":"Ten-year update of the international registry on cytokine-induced killer cells in cancer immunotherapy","volume":"235","author":"Zhang","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100508","DOI":"10.1016\/j.xcrm.2022.100508","article-title":"Autologous NK cells as consolidation therapy following stem cell transplantation in multiple myeloma","volume":"3","author":"Nahi","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s40425-017-0305-7","article-title":"Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial","volume":"5","author":"Canter","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Judge, S.J., Yanagisawa, M., Sturgill, I.R., Bateni, S.B., Gingrich, A.A., Foltz, J.A., Lee, D.A., Modiano, J.F., Monjazeb, A.M., and Culp, W.T.N. (2020). Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0224775"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"147","DOI":"10.4314\/ovj.v9i2.9","article-title":"Lymphokine-activated killer cell transplantation after anti-cancer treatment in two aged cats","volume":"9","author":"Maeta","year":"2019","journal-title":"Open Vet. J."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Shiozawa, M., Chang, C.-H., Huang, Y.-C., Chen, Y.-C., Chi, M.-S., Hao, H.-C., Chang, Y.C., Takeda, S., Chi, K.H., and Wang, Y.S. (2018). Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. BMC Immunol., 19.","DOI":"10.1186\/s12865-018-0262-z"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/vco.12032","article-title":"Response evaluation criteria for solid tumours in dogs (v1.0): A Veterinary Cooperative Oncology Group (VCOG) consensus document","volume":"13","author":"Nguyen","year":"2015","journal-title":"Vet. Comp. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Veterinary Cooperative Oncology Group (2016). Common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biological antineoplastic therapy in dogs and cats v1.1. Vet. Comp. Oncol., 14, 417\u2013446.","DOI":"10.1111\/vco.283"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/vco.12677","article-title":"Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats","volume":"19","author":"LeBlanc","year":"2021","journal-title":"Vet. Comp. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/vco.12761","article-title":"Prognostic impact of bone invasion in canine oral malignant melanoma treated by surgery and anti-CSPG4 vaccination: A retrospective study on 68 cases (2010\u20132020)","volume":"20","author":"Camerino","year":"2022","journal-title":"Vet. Comp. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/vco.12815","article-title":"A retrospective study of 101 dogs with oral melanoma treated with a weekly or biweekly 6 Gy \u00d7\u20096 radiotherapy protocol","volume":"20","author":"Baja","year":"2022","journal-title":"Vet. Comp. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1111\/vco.12827","article-title":"Diagnosis and histopathologic prognostication of canine melanocytic neoplasms: A consensus of the Oncology-Pathology Working Group","volume":"20","author":"Smedley","year":"2022","journal-title":"Vet. Comp. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"670309","DOI":"10.3389\/fimmu.2021.670309","article-title":"Comparative immunogenomics of canine natural killer cells as immunotherapy target","volume":"12","author":"Gingrich","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/j.1476-5829.2012.00338.x","article-title":"Use of adjuvant carboplatin for treatment of dogs with oral malignant melanoma following surgical excision","volume":"12","author":"Dank","year":"2014","journal-title":"Vet. Comp. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/vru.12860","article-title":"Multimodality treatment including ONCEPT for canine oral melanoma: A retrospective analysis of 131 dogs","volume":"61","author":"Turek","year":"2020","journal-title":"Vet. Radiol. Ultrasound"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Husman, T., Cen, X., Tsao, T., Brown, J., Bajpai, A., Li, M., Zhou, K., and Yang, L. (2022). Interleukin 15 in cell-based cancer immunotherapy. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23137311"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/S1470-2045(17)30251-6","article-title":"Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: A single-centre, two-stage, single-arm, phase 2 study","volume":"18","author":"Chandran","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.vetimm.2013.06.013","article-title":"Isolation and characterization of canine natural killer cells","volume":"155","author":"Michael","year":"2013","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00262-004-0555-3","article-title":"Natural killer (NK) and lymphokine-activated killer (LAK) cell functions from healthy dogs and 29 dogs with a variety of spontaneous neoplasms","volume":"54","author":"Funk","year":"2005","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e005678","DOI":"10.1136\/jitc-2022-005678","article-title":"Dose-response correlation for CAR-T cells: A systematic review of clinical studies","volume":"10","author":"Rotte","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1080\/21645515.2017.1285987","article-title":"Cell-based immunotherapy with cytokine-induced killer (CIK) cells: From preparation and testing to clinical application","volume":"13","author":"Meng","year":"2017","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine Storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Noguchi, S., Yagi, K., Okamoto, N., Wada, Y., and Tanaka, T. (2022). Prognostic factors for the efficiency of radiation therapy in dogs with oral melanoma: A pilot study of hypoxia in intraosseous lesions. Vet. Sci., 10.","DOI":"10.3390\/vetsci10010004"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gingrich, A.A., Modiano, J.F., and Canter, R.J. (2019). Characterization and potential applications of dog natural killer cells in cancer immunotherapy. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111802"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Guo, Q., Zhu, D., Bu, X., Wei, X., Li, C., Gao, D., Wei, X., Ma, X., and Zhao, P. (2017). Efficient killing of radioresistant breast cancer cells by cytokine-induced killer cells. Tumor Biol., 39.","DOI":"10.1177\/1010428317695961"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s00262-014-1566-3","article-title":"Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer","volume":"63","author":"Chung","year":"2014","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/CJI.0b013e318241d9de","article-title":"Autologous cytokine-induced killer cell transfusion in combination with gemcitabine plus cisplatin regimen chemotherapy for metastatic nasopharyngeal carcinoma","volume":"35","author":"Li","year":"2012","journal-title":"J. Immunother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.21873\/anticanres.14376","article-title":"Cytokine-induced killer T cells enhance the cytotoxicity against carboplatin-resistant ovarian cancer cells","volume":"40","author":"Pan","year":"2020","journal-title":"Anticancer. Res."}],"container-title":["Veterinary Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-7381\/11\/4\/150\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:20:10Z","timestamp":1760106010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-7381\/11\/4\/150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,28]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["vetsci11040150"],"URL":"https:\/\/doi.org\/10.3390\/vetsci11040150","relation":{},"ISSN":["2306-7381"],"issn-type":[{"value":"2306-7381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,28]]}}}