title: Development of an allogeneic whole-cell tumor vaccine expressing xenogeneic gp100 and its implementation in a phase II clinical trial in canine patients with malignant melanoma.
abstract: A xenogeneic melanoma-antigen-enhanced allogeneic tumor cell vaccine (ATCV) is an appealing strategy for anti-cancer immunotherapy due to its relative ease of production, and the theoretical possibility that presentation of a multiplex of antigens along with a xenogeneic antigen would result in cross-reaction between the xenogeneic homologs and self-molecules, breaking tolerance and ultimately resulting in a clinically relevant immune response. In this study, we evaluated the efficacy of such a strategy using a xenogeneic melanoma differentiation antigen, human glycoprotein 100 (hgp100) in the context of a phase II clinical trial utilizing spontaneously arising melanoma in pet dogs. Our results demonstrate that the approach was well tolerated and resulted in an overall response rate (complete and partial response) of 17% and a tumor control rate (complete and partial response and stable disease of >6 weeks duration) of 35%. Dogs that had evidence of tumor control had significantly longer survival times than dogs that did not experience control. Delayed type hypersensitivity (DTH) to 17CM98 canine melanoma cells used in the whole cell vaccine was enhanced by ATCV and correlated with clinical response. In vitro cytotoxicity was enhanced by ATCV, but did not correlate with clinical response. Additionally, anti-hgp100 antibodies were elicited in response to ATCV in the majority of patients tested; however, this also did not correlate with clinical response. This approach, along with further elucidation of the mechanisms of tumor protection after xenogeneic immunization, may allow the development of more rational vaccines. This trial also further demonstrates the utility of spontaneous tumors in companion animals as a valid translational model for the evaluation of novel vaccine therapies.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI, 53706, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Alexander
authors.forename: M K
authors.initials: MK
authors.lastname: Huelsmeyer
authors.forename: Ann
authors.initials: A
authors.lastname: Mitzey
authors.forename: R R
authors.initials: RR
authors.lastname: Dubielzig
authors.forename: I D
authors.initials: ID
authors.lastname: Kurzman
authors.forename: E G
authors.initials: EG
authors.lastname: Macewen
authors.forename: D M
authors.initials: DM
authors.lastname: Vail
mesh_terms: D000818:Animals; D015478:Antigens, Heterophile; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D004283:Dog Diseases / Q000276:immunology* / Q000628:therapy*; D004285:Dogs; D008545:Melanoma / Q000276:immunology* / Q000628:therapy* / Q000662:veterinary; D008562:Membrane Glycoproteins / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000276:immunology* / Q000628:therapy* / Q000662:veterinary; D013534:Survival; D014162:Transfection; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D058951:gp100 Melanoma Antigen
chemical_list: D015478:Antigens, Heterophile; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D058951:gp100 Melanoma Antigen