A novel mouse model for identification of HLA-A2.1 epitopes and evaluation of CEA cancer vaccine
Authors: Luigi Aurisicchio, Patrizia Giannetti, Daniela Peruzzi, Gennaro Ciliberto, Nicola La Monica
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4878 

CEA is a 180KDa glycoprotein over-expressed in a high percentage of adenocarcinomas and is currently under evaluation in clinical trials as target for immunotherapy in the treatment of colorectal cancer. An absolute requirement for an effective vaccination strategy targeting CEA is to overcome the immunologic tolerance. Pre-clinical studies cancer vaccine studies have been conducted so far in transgenic mice expressing the human tumor antigen and breaking tolerance requires aggressive and efficient strategies such as genetic vaccines. Among them, in vivo electroporation (EP) of plasmid DNA as well as replication-defective recombinant Ad have been shown to be safe and to induce strong humoral and cellular antigen-specific immune responses. However, because human MHC class I alleles are distinct from those of mice, animals transgenic for only CEA are not suitable for prediction of effective immunological correlates and testing HLA-A2-restricted vaccines. The most widely used and effective mouse model to test HLA-A2.1 restricted immune response are the HHD mice developed by F. Lemonnier at Pasteur institute: such mice express 1 and 2 domains of the human HLA-A2.1 molecule fused to the 3 domain from the mouse H-2Db molecule and to human β2-microglobulin. This molecular complex is functional for efficient epitope presentation. However, mice transgenic only for HHD are unsuitable for in vivo studies of HLA-A2-restricted, CEA-specific responses because these animals recognize CEA as a foreign antigen and lack central and peripheral T cell tolerance. For this reason, we generated HHD/CEA double transgenic mice by breeding transgenic mice homozygous for CEA and HHD. These mice express human CEA antigen presented exclusively by human HLA-A2 molecules. In fact, since these mice are transgenic for CEA, for HHD and lack mouse β2-microglobulin, they represent a unique in vivo animal model to study human immune response of a human CEA-based vaccine. Notably, our model differ from other mice where mouse MHC-I is still present and immunogenic and therapeutic efficacy may be hampered by mouse/human haplotype specificity and competition phenomena. Our data show that genetic vectors expressing CEA derivatives are able to efficiently break immune tolerance against CEA and to elicit strong immune response against known and novel HLA-A2.1 restricted CEA epitopes. Moreover, peptide-based vaccine resulted in effective responses against selected epitopes within the tumor antigen. Most importantly, significant protection was obtained in vaccinated mice upon B16-HHD-CEA tumor cell challenge, a tumor model in which human CEA epitopes are processed and presented by HHD molecule In conclusion, we have developed CEA transgenic mice expressing CEA as a self-antigen with a tissue distribution similar to that of humans which provides a relevant model for the evaluation of the potential efficacy of a human CEA-based vaccine.