Preclinical Qualification of a New Multi-antigen Candidate Vaccine for Metastatic Melanoma

• Published in: Journal of immunotherapy (1997) Vol. 33; no. 8; pp. 743 - 758
• Main Authors: VOGEL, Thorsten U, VISAN, Lucian, MCNEIL, Bryan, SANDHU, Devender, SCOLLARD, Nancy, LINONG ZHANG, BRADLEY, Bill, MEI TANG, LOVITT, Corey, OOMEN, Ray, DUNN, Pamela, TARTAGLIA, Jim, LJUTIC, Belma, BERINSTEIN, Neil L, GAJEWSKA, Beata, CATERINI, Judy, SALHA, Danielle, TAO WEN, LIWEI HE, PARRINGTON, Mark, CAO, Shi-Xian
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-10-2010
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines; Cells, Cultured; Cloning, Molecular; Cytotoxicity, Immunologic; Dermatology; Drug Evaluation, Preclinical; HLA-A2 Antigen - genetics; Humans; Immunotherapy; Lymphocyte Activation; Medical sciences; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Mice; Mice, Transgenic; Neoplasm Metastasis; Pharmacology. Drug treatments; Poxviridae - genetics; Poxviridae - immunology; Poxviridae - pathogenicity; Poxviridae Infections - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - pathology; Tumors of the skin and soft tissue. Premalignant lesions; Viral Vaccines; cancer vaccines; Preclinical trial; melanoma; Vaccine; TRICOM; Metastasis; Malignant tumor; T cells; Antigen; Treatment; Immunotherapy; T-Lymphocyte; Malignant melanoma; Advanced stage; ALVAC; Cancer
• ISSN: 1524-9557; 1537-4513
• DOI: 10.1097/CJI.0b013e3181eccc87

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.