A Mouse Model Of Chimeric NY-ESO-1 DNA Vaccine For The Treatment Of Melanoma

The cancer-testis antigen NY-ESO-1 is one of the most immunogenic tumor antigens and is therefore an attractive candidate for cancer vaccines. However, to date peptide and protein vaccines using NY-ESO-1 antigen have generated unsatisfactory clinical outcomes and improvements in vaccine design are therefore needed for efficient cancer immunotherapy using this antigen. Here we have utilized electroporation enhanced delivery in C57BL/ 6 mice to screen different chimeric vaccine designs, in which NY-ESO-1 is expressed as an in-frame fusion with proteins that impact antigen processing, trafficking or presentation with the aim to identify an improved genetic adjuvant for this antigen. We found that plasmids encoding NY-ESO-1 alone or linked with HSP70 induced strong NY-ESO-1-specific Ig G1 response., Mice immunized with plasmid encoding ubiquitin linked NY-ESO-1, however, induced primarily a NY-ESO-1-specific Ig G2 a response indicating that this genetic adjuvant drives the immune system towards a strong Th1 response. Mice immunized with plasmid encoding ubiquitin linked NY-ESO-1 followed by electroporation showed significant improved protection against challenge with a B16F10 melanoma cell line expressing NY-ESO-1 as compared to other chimeric NY-ESO-1 vaccine constructs demonstrating the importance of a strong Th1 response in tumor protection. Depletion of regulatory T(Treg) cells by denileukin diftitox(ONTAK) further enhanced the antitumor effect of the ubiquitin linked NY-ESO-1 DNA vaccine in a therapeutic study. Finally, combining ubiquitin-linked NY-ESO-1 construct with plasmids encoding the xenogenic versions of the melanoma antigens(gp100 and TRP-2) induced a synergic antitumor effect against NY-ESO-1 expressing B16F10 tumor. Overall, these data suggests that p DNA encoding the ubiquitin linked NY-ESO-1, alone or in combination with other relevant melanoma antigens may be a potent therapeutic cancer vaccine.