{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T03:34:30Z","timestamp":1791603270782,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T00:00:00Z","timestamp":1691020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"publisher","award":["2018-11651"],"award-info":[{"award-number":["2018-11651"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>It was recently shown that targeting extracellular vimentin (eVim) is safe and effective in preclinical models. Here, we report the safety and efficacy in client-owned dogs with spontaneous bladder cancer of CVx1, an iBoost technology-based vaccine targeting eVim in combination with COX-2 inhibition. This was a single-arm prospective phase 1\/2 study with CVx1 in 20 client-owned dogs with spontaneous UC which involved four subcutaneous vaccinations with CVx1 at 2-week intervals for induction of antibody titers, followed by maintenance vaccinations at 2-month intervals. Additionally, daily cyclooxygenase (COX)-2 inhibition with meloxicam was given. The response was assessed by antibody titers, physical condition, abdominal ultrasound and thorax X-ray. The primary endpoints were the development of antibody titers, as well as overall survival compared to a historical control group receiving carboplatin and COX-2 inhibition with piroxicam. Kaplan\u2013Meier survival analysis was performed. All dogs developed antibodies against eVim. Titers were adequately maintained for the duration of this study. A median overall survival of 374 days was observed, which was 196 days for the historical control group (p &lt; 0.01). Short-term grade 1\u20132 toxicity at the injection site and some related systemic symptoms peri-vaccination were observed. No toxicity was observed related to the induced antibody response. A limitation of this study is the single-arm prospective setting. CVx1 plus meloxicam consistently induced efficient antibody titers, was well tolerated and showed prolonged survival. The results obtained merit further development for human clinical care.<\/jats:p>","DOI":"10.3390\/cancers15153958","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T11:23:03Z","timestamp":1691061783000},"page":"3958","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Vaccination against Extracellular Vimentin for Treatment of Urothelial Cancer of the Bladder in Client-Owned Dogs"],"prefix":"10.3390","volume":"15","author":[{"given":"Diederik J. M.","family":"Engbersen","sequence":"first","affiliation":[{"name":"CimCure BV, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4309-3713","authenticated-orcid":false,"given":"Judy R.","family":"van Beijnum","sequence":"additional","affiliation":[{"name":"CimCure BV, 1081 HV Amsterdam, The Netherlands"},{"name":"Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno","family":"Roos","sequence":"additional","affiliation":[{"name":"Veterinary Referral Center Korte Akkeren, 2802 LA Gouda, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marit","family":"van Beelen","sequence":"additional","affiliation":[{"name":"Veterinary Referral Center Korte Akkeren, 2802 LA Gouda, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan David","family":"de Haan","sequence":"additional","affiliation":[{"name":"Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-9648","authenticated-orcid":false,"given":"Guy C. M.","family":"Grinwis","sequence":"additional","affiliation":[{"name":"Veterinary Pathology Diagnostic Centre, Department of Biomedical Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 TD Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A.","family":"Schalken","sequence":"additional","affiliation":[{"name":"Department of Urology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Alfred","family":"Witjes","sequence":"additional","affiliation":[{"name":"Department of Urology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8508-4754","authenticated-orcid":false,"given":"Arjan W.","family":"Griffioen","sequence":"additional","affiliation":[{"name":"CimCure BV, 1081 HV Amsterdam, The Netherlands"},{"name":"Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7742-9839","authenticated-orcid":false,"given":"Elisabeth J. M.","family":"Huijbers","sequence":"additional","affiliation":[{"name":"CimCure BV, 1081 HV Amsterdam, The Netherlands"},{"name":"Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1007\/s00345-019-02984-4","article-title":"The global burden of urinary bladder cancer: An update","volume":"38","author":"Richters","year":"2020","journal-title":"World J. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00345-009-0395-z","article-title":"Economic aspects of bladder cancer: What are the benefits and costs?","volume":"27","author":"Sievert","year":"2009","journal-title":"World J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.eururo.2015.10.024","article-title":"Economic Burden of Bladder Cancer Across the European Union","volume":"69","author":"Leal","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.eururo.2014.01.006","article-title":"The economics of bladder cancer: Costs and considerations of caring for this disease","volume":"66","author":"Svatek","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17022","DOI":"10.1038\/nrdp.2017.22","article-title":"Bladder cancer","volume":"3","author":"Sanli","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.eururo.2020.03.055","article-title":"European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines","volume":"79","author":"Witjes","year":"2021","journal-title":"Eur. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Saginala, K., Barsouk, A., Aluru, J.S., Rawla, P., Padala, S.A., and Basouk, A. (2020). Epidemiology of Bladder Cancer. Med. Sci., 8.","DOI":"10.3390\/medsci8010015"},{"key":"ref_9","first-page":"103","article-title":"Role of immunotherapy in bacillus Calmette\u2013Gu\u00e9rin-unresponsive non\u2013muscle invasive bladder cancer","volume":"36","author":"Mukherjee","year":"2018","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"404","DOI":"10.3322\/caac.21631","article-title":"Treatment of muscle-invasive and advanced bladder cancer in 2020","volume":"70","author":"Patel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Roviello, G., Catalano, M., Santi, R., Palmieri, V.E., Vannini, G., Galli, I.C., Buttitta, E., Villari, D., Rossi, V., and Nesi, G. (2021). Immune checkpoint inhibitors in urothelial bladder cancer: State of the art and future perspectives. Cancers, 13.","DOI":"10.3390\/cancers13174411"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4582","DOI":"10.1016\/j.vaccine.2005.08.027","article-title":"Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center","volume":"24","author":"Bergman","year":"2006","journal-title":"Vaccine"},{"key":"ref_13","unstructured":"Vail, D.M., Thamm, D.H., and Liptak., J.M. (2020). Withrow and MacEwen\u2019s Small Animal Clinical Oncology, Elsevier. [6th ed.]."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.1038\/s41467-022-30063-7","article-title":"Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy","volume":"13","author":"Huijbers","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1182\/blood-2006-02-004291","article-title":"Gene expression of tumor angiogenesis dissected: Specific targeting of colon cancer angiogenic vasculature","volume":"108","author":"Dings","year":"2006","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1016\/j.vaccine.2018.03.064","article-title":"An improved conjugate vaccine technology; induction of antibody responses to the tumor vasculature","volume":"36","author":"Huijbers","year":"2018","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Van Loon, K., Huijbers, E.J.M., de Haan, J.D., and Griffioen, A.W. (2022). Cancer Vaccination against Extracellular Vimentin Efficiently Adjuvanted with Montanide ISA 720\/CpG. Cancers, 14.","DOI":"10.3390\/cancers14112593"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jcpa.2006.07.002","article-title":"Classification of Canine Urinary Bladder Urothelial Tumours Based on the World Health Organization\/International Society of Urological Pathology Consensus Classification","volume":"135","author":"Patrick","year":"2006","journal-title":"J. Comp. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.3389\/fonc.2019.01493","article-title":"Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans","volume":"9","author":"Knapp","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.3389\/fimmu.2019.02935","article-title":"A Role for Dogs in Advancing Cancer Immunotherapy Research","volume":"10","author":"Dow","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1476-5810.2005.00070.x","article-title":"Carboplatin and piroxicam therapy in 31 dogs with transitional cell carcinoma of the urinary bladder","volume":"3","author":"Boria","year":"2005","journal-title":"Vet. Comp. Oncol."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.tvjl.2017.12.008","article-title":"Evaluation of two-dimensional ultrasonography and computed tomography in the mapping and measuring of canine urinary bladder tumors","volume":"232","author":"Honkisz","year":"2018","journal-title":"Vet. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/vco.12677","article-title":"Veterinary Cooperative Oncology Group\u2014Common 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_25","doi-asserted-by":"crossref","first-page":"204759","DOI":"10.1155\/2015\/204759","article-title":"Association of cytokeratin and vimentin protein in the genesis of transitional cell carcinoma of urinary bladder patients","volume":"2015","author":"Rahmani","year":"2015","journal-title":"Dis. Markers"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3233\/BLC-150044","article-title":"A nonselective cyclooxygenase inhibitor enhances the activity of vinblastine in a naturally-occurring canine model of invasive urothelial carcinoma","volume":"2","author":"Knapp","year":"2016","journal-title":"Bladder Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s002800000147","article-title":"Cisplatin versus cisplatin combined with piroxicam in a canine model of human invasive urinary bladder cancer","volume":"46","author":"Knapp","year":"2000","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/jvim.12533","article-title":"Randomized Phase III Trial of Piroxicam in Combination with Mitoxantrone or Carboplatin for First-Line Treatment of Urogenital Tract Transitional Cell Carcinoma in Dogs","volume":"29","author":"Allstadt","year":"2015","journal-title":"J. Vet. Intern. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1939-1676.1994.tb03232.x","article-title":"Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder","volume":"8","author":"Knapp","year":"1994","journal-title":"J. Vet. Intern. Med."},{"key":"ref_30","first-page":"906","article-title":"Clinical evaluation of mitoxantrone and piroxicam in a canine model of human invasive urinary bladder carcinoma","volume":"9","author":"Henry","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/jsap.12009","article-title":"Retrospective evaluation of doxorubicin-piroxicam combination for the treatment of transitional cell carcinoma in dogs","volume":"54","author":"Robat","year":"2013","journal-title":"J. Small Anim. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.2460\/javma.238.8.1004","article-title":"Toxic effects and antitumor response of gemcitabine in combination with piroxicam treatment in dogs with transitional cell carcinoma of the urinary bladder","volume":"238","author":"Marconato","year":"2011","journal-title":"J. Am. Vet. Med. Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1177\/03009858221117858","article-title":"Vimentin and Ki-67 immunolabeling in canine gastric carcinomas and their prognostic value","volume":"59","author":"Flores","year":"2022","journal-title":"Vet. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1096\/fj.10-163022","article-title":"Vaccination against the extra domain-B of fibronectin as a novel tumor therapy","volume":"24","author":"Huijbers","year":"2010","journal-title":"FASEB J."},{"key":"ref_35","first-page":"1111","article-title":"Endothelial intercellular adhesion molecule-1 expression is suppressed in human malignancies: The role of angiogenic factors","volume":"56","author":"Griffioen","year":"1996","journal-title":"Cancer Res."},{"key":"ref_36","first-page":"279","article-title":"Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy","volume":"26","author":"Griffioen","year":"2022","journal-title":"Angiogenesis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"eabm6388","DOI":"10.1126\/sciimmunol.abm6388","article-title":"Tumors resurrect an embryonic vascular program to escape immunity","volume":"7","author":"Huijbers","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_38","unstructured":"Fulkerson, C.E., and Knapp, D.W. (2020). Withrow and MacEwen\u2019s Small Animal Clinical Oncology, Elsevier. [6th ed.]."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"37042","DOI":"10.18632\/oncotarget.26455","article-title":"Phase I\/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma","volume":"9","author":"Szigetvari","year":"2018","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"243","DOI":"10.5326\/JAAHA-MS-6905","article-title":"Use of Toceranib Phosphate in the Treatment of Canine Bladder Tumors: 37 Cases","volume":"55","author":"Biller","year":"2019","journal-title":"J. Am. Anim. Hosp. Assoc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1093\/ilar\/ilu018","article-title":"Urinary bladder cancer in dogs, a naturally occuring model for cancer biology and drug development","volume":"55","author":"Knapp","year":"2014","journal-title":"ILAR J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/vco.12483","article-title":"Survival analysis in dogs with urinary transitional cell carcinoma that underwent whole-body computed tomography at diagnosis","volume":"17","author":"Iwasaki","year":"2019","journal-title":"Vet. Comp. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cvsm.2018.11.006","article-title":"Urologic Oncology","volume":"49","author":"Burgess","year":"2019","journal-title":"Vet. Clin. N. Am. Small Anim. Pract."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.provac.2009.07.026","article-title":"Adjuvant formulation for veterinary vaccines: MontanideTM Gel safety profile","volume":"1","author":"Parker","year":"2009","journal-title":"Procedia Vaccinol."},{"key":"ref_45","unstructured":"NIH US National Library of Medicine (2022, November 02). CpG 7909\/Montanide ISA 720 with or without Cyclophosphamide in Combination Either with NY-ESO-1-derived Peptides or the NY-ESO-1 Protein for NY-ESO-1-expressing Tumors (NCT00819806), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00819806."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/15\/3958\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:25:16Z","timestamp":1760127916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/15\/3958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,3]]},"references-count":45,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["cancers15153958"],"URL":"https:\/\/doi.org\/10.3390\/cancers15153958","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,3]]}}}