Genetic vaccines against Ep‐CAM break tolerance to self in a limited subset of subjects: Initial identification of predictive biomarkers

• Published in: European Journal of Immunology 2006-05, Vol.36 (5), p.1337-1349
• Main Authors: Elia, Leonardo, Mennuni, Carmela, Storto, Mariangela, Podda, Silvia, Calvaruso, Francesco, Salucci, Valentina, Aurisicchio, Luigi, Scarito, Alessia, Ciliberto, Gennaro, Monica, Nicola La, Palombo, Fabio
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Amino Acid Sequence; Animals; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Biomarkers; Cancer vaccine; Cancer Vaccines - immunology; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - immunology; Cell‐mediated immune response; Epithelial Cell Adhesion Molecule; Immune Tolerance; Macaca mulatta; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Sequence Data; Tumor‐associated antigen; Vaccination; Vaccines, DNA - immunology; Vaccines, Synthetic - immunology
• ISSN: 0014-2980; 1521-4141; 1365-2567
• DOI: 10.1002/eji.200535514

The epithelial cell adhesion molecule, Ep‐CAM, has been historically considered a target of passive immunotherapy using monoclonal antibodies, and more recently, of a first Pox‐vector‐based cancer vaccine Phase I trial in colorectal cancer patients. To shed further light on the use of this antigen, we isolated the mouse and rhesus homologues of human Ep‐CAM and explored different genetic vaccination modalities based on the use of adenoviral vectors as well as DNA electroporation (DNA‐EP). Immune responses to Ep‐CAM were measured by IFN‐γ ELISPOT and intracellular staining assays using overlapping sets of peptides covering the entire coding regions. We found the most powerful vaccination regimen to be constituted by DNA‐EP‐prime/Adeno‐boost mixed‐modality protocols. Vaccination in rhesus macaques resulted in breakage of immunological tolerance in a minority of cases. Similarly, a low frequency of responders was observed with the mouse Ep‐CAM vaccine in outbred CD1 mice. When immunized CD1 mice were analyzed for MHC haplotype and TCR expression levels, we observed that immune responders all had the same q/q MHC class I haplotype and showed higher expression levels of the TCRVβ4 and TCRVβ8 T cell receptors. Our results underscore the current limitations in our capacity to induce efficient cancer vaccines against self antigens like Ep‐CAM, but also represent a first effort to identify predictive biomarkers of response. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636085