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

Leonardo Elia, Carmela Mennuni, Mariangela Storto, Silvia Podda, Francesco Calvaruso, Valentina Salucci, Luigi Aurisicchio, Alessia Scarito, Gennaro Ciliberto, Nicola La Monica, Fabio Palombo

Research output: Contribution to journalArticle

Abstract

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 CAM, but also represent a first effort to identify predictive biomarkers of response.

Original languageEnglish
Pages (from-to)1337-1349
Number of pages13
JournalEuropean Journal of Immunology
Volume36
Issue number5
DOIs
Publication statusPublished - May 2006

Keywords

  • Cancer vaccine
  • Cell-mediated immune response
  • Tumor-associated antigen

ASJC Scopus subject areas

  • Immunology

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    Elia, L., Mennuni, C., Storto, M., Podda, S., Calvaruso, F., Salucci, V., Aurisicchio, L., Scarito, A., Ciliberto, G., La Monica, N., & Palombo, F. (2006). Genetic vaccines against Ep-CAM break tolerance to self in a limited subset of subjects: Initial identification of predictive biomarkers. European Journal of Immunology, 36(5), 1337-1349. https://doi.org/10.1002/eji.200535514