Genetic vaccines against Ep-CAM break tolerance to self in a limited subset of subjects: initial identification of predictive biomarkers.
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-gamma 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 TCRVbeta4 and TCRVbeta8 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.
Elia
Leonardo
L
Molecular and Cellular Biology Department, IRBM P. Angeletti, Pomezia, Italy.
Mennuni
Carmela
C
Storto
Mariangela
M
Podda
Silvia
S
Calvaruso
Francesco
F
Salucci
Valentina
V
Aurisicchio
Luigi
L
Scarito
Alessia
A
Ciliberto
Gennaro
G
La Monica
Nicola
N
Palombo
Fabio
F
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D015415:Biomarkers; D019496:Cancer Vaccines / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D000071858:Epithelial Cell Adhesion Molecule; D007108:Immune Tolerance; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*
D000951:Antigens, Neoplasm; D015415:Biomarkers; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic