title: Preclinical qualification of a new multi-antigen candidate vaccine for metastatic melanoma.
abstract: New therapies are urgently required for the treatment of patients with melanoma. Here we describe the generation and preclinical evaluation of 3 new recombinant ALVAC(2) poxviruses vCP2264, vCP2291, and vCP2292 for their ability to induce the desired cellular immune responses against the encoded melanoma-associated antigens. This was done either in HLA-A2/K transgenic mice or using in vitro antigen-presentation studies. These studies demonstrated that the vaccine was able to induce HLA-A*0201-restricted T-cell responses against gp100 and NY-ESO-1, detectable directly ex vivo, in HLA-A2/K-transgenic mice. The in vitro antigen presentation studies, in the absence of appropriate animal models, demonstrated that target cells infected with the vaccine construct were lysed by MAGE-1, MAGE-3 or MART-1 peptide-specific T cells. These data indicate that ALVAC(2)-encoded melanoma-associated antigens can be properly processed and presented to induce antigen-specific cytotoxic T-cell responses. To enhance the immunogenicity of the melanoma antigens, a TRIad of COstimulatory Molecules (TRICOM) were also cloned into all 3 vectors. Increased in vitro proliferation and IFN-γ production was observed with all ALVAC(2) poxviruses encoding TRICOM, confirming the immune-enhancing effect of the ALVAC-encoded TRICOM. These studies demonstrated that all components of the vaccine were functionally active and provide a rationale for moving this candidate vaccine to the clinic.
authors.affiliation: Sanofi Pasteur, Toronto, Ontario, Canada. thorsten.vogel@sanofipasteur.com
authors.forename: Thorsten U
authors.initials: TU
authors.lastname: Vogel
authors.forename: Lucian
authors.initials: L
authors.lastname: Visan
authors.forename: Belma
authors.initials: B
authors.lastname: Ljutic
authors.forename: Beata
authors.initials: B
authors.lastname: Gajewska
authors.forename: Judy
authors.initials: J
authors.lastname: Caterini
authors.forename: Danielle
authors.initials: D
authors.lastname: Salha
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Liwei
authors.initials: L
authors.lastname: He
authors.forename: Mark
authors.initials: M
authors.lastname: Parrington
authors.forename: Shi-Xian
authors.initials: SX
authors.lastname: Cao
authors.forename: Bryan
authors.initials: B
authors.lastname: McNeil
authors.forename: Devender
authors.initials: D
authors.lastname: Sandhu
authors.forename: Nancy
authors.initials: N
authors.lastname: Scollard
authors.forename: Linong
authors.initials: L
authors.lastname: Zhang
authors.forename: Bill
authors.initials: B
authors.lastname: Bradley
authors.forename: Mei
authors.initials: M
authors.lastname: Tang
authors.forename: Corey
authors.initials: C
authors.lastname: Lovitt
authors.forename: Ray
authors.initials: R
authors.lastname: Oomen
authors.forename: Pamela
authors.initials: P
authors.lastname: Dunn
authors.forename: Jim
authors.initials: J
authors.lastname: Tartaglia
authors.forename: Neil L
authors.initials: NL
authors.lastname: Berinstein
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003602:Cytotoxicity, Immunologic; D004353:Drug Evaluation, Preclinical; D015789:HLA-A2 Antigen / Q000235:genetics; D006801:Humans; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011212:Poxviridae / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D011213:Poxviridae Infections / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014765:Viral Vaccines
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D014765:Viral Vaccines