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

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-c 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 mixedmodality 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 TCRVb4 and TCRVb8 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

Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer

“…Previous studies have shown successful immunotherapy for tumors in a cross-reaction between the xenogeneic homologues and self-molecules in a mouse model (43). In a recent study, mice vaccinated with Ad-hEp-CAM (epithelial cell adhesion molecule) or Ad-rhEp-CAM were protected from a tumor challenge with MC38-hEp-CAM cells; this showed that the immune response induced against hEp-CAM with both vaccines is sufficient to produce a biological antitumor effect (44). VLPs have the capacity to break self-tolerance to produce antibody responses against self-proteins expressed on them (45).…”

Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways

“…After 16 h medium was changed, and recombinant lentivirus vectors were harvested 48 h later. FACS analysis was conducted as previously described [15]. …”

Optimizing cancer immunotherapy trials: Back to basics

“…One reason for the ability of xenogeneic antigen to break tolerance, as described in the paper in this issue of the European Journal of Immunology by Leonardo et al [8], is likely to be the presence of some foreign sequence in the xenogeneic antigen that is able to activate Th cells; however, this is rather a 'hit and miss' approach to breaking tolerance for therapeutic purposes since the degree of difference between self and xenogeneic antigen is often small and might be sufficient to induce an immune response only in a minority of patients with a suitable MHC Class II background. The variable performance of the mouse Ep-CAM vaccine in outbred mice described in the study by Lenardo et al [8] could reflect this heterogeneity.…”

“…One of these is electroporation, which has been shown to increase performance in large animals, including rhesus macaques [14]. Leonardo et al [8] use electroporation but combine it with a boost using a viral vector. The latter, however, introduces the problem of immunity against viral proteins which may be pre-existing and can block any boosting [15].…”

“…Leonardo et al [8] have selected Ep-CAM as a target antigen. This is expressed at the cell surface and therefore should be susceptible to antibody attack.…”