Prime/boost immunotherapy of HPV16-induced tumors with E7 protein delivered by Bordetella adenylate cyclase and modified vaccinia virus ankara

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2006-01, Vol.55 (1), p.39-46
• Main Authors: MACKOVA, Jana, STASIKOVA, Jana, KUTINOVA, Luda, MASIN, Jiri, HAINZ, Petr, SIMSOVA, Marcela, GABRIEL, Pavel, SEBO, Peter, NEMECKOVA, Sarka
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Adenylate Cyclase Toxin; Animals; Antigen presentation; Antigen processing; Antigen-presenting cells; Antigens; Antigens, Neoplasm; Antigens, Viral; Antineoplastic agents; Biological and medical sciences; Bordetella; Cancer; Cancer Vaccines - immunology; CD11b antigen; CD18 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cytosol; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; E7 protein; Female; Human papillomavirus; Human papillomavirus 16; Human papillomavirus 16 - pathogenicity; Immune response (cell-mediated); Immunity, Cellular; Immunization, Secondary; Immunotherapy; Immunotherapy - methods; Lymphocytes T; Mac1 protein; Major histocompatibility complex; Medical sciences; Membrane proteins; Mice; Mice, Inbred C57BL; Oncogene Proteins, Viral - immunology; Original; Papillomavirus E7 Proteins; Pharmacology. Drug treatments; Proteins; Tumor cells; Tumor Cells, Cultured; Tumors; Vaccination; Vaccines; Vaccinia virus; Viruses
• ISSN: 0340-7004; 1432-0851; 1365-2567
• DOI: 10.1007/s00262-005-0700-7

The Bordetella adenylate cyclase toxoid (CyaA) targets cells expressing the alphaMbeta2 integrin receptor CD11b/CD18 (CR3 or Mac-1) and can penetrate into cytosol of professional antigen-presenting cells, such as dendritic cells. This allows us to use CyaA for delivery of passenger antigens into the cytosolic pathway of processing and MHC class I-restricted presentation, which can promote induction of antigen-specific CD8+ cytotoxic T-lymphocyte immune responses. We show here that vaccination with a genetically detoxified CyaA336/E7 protein, carrying the full-length oncoprotein E7 of the human papilloma virus 16 inserted at position 336 of the cell-invasive AC domain of CyaA, induces an E7-specific CD8+ T-cell immune response and confers on mice protective, as well as therapeutic immunity against challenge with TC-1 tumor cells expressing the E7 oncoprotein. The therapeutic efficacy of priming with the CyaA336/E7 vaccine could further be enhanced by a heterologous booster immunization with a highly attenuated modified vaccinia virus Ankara (MVA) expressing the E7 protein fused to the lysosome-associated membrane protein (LAMP1). These results establish the potential of CyaA as a new antigen delivery tool for prime/boost immunotherapy of tumors.