Optimal organization of a polypeptide-based candidate cancer vaccine composed of cryptic tumor peptides with enhanced immunogenicity

Polyspecific tumor vaccination should offer broad control of tumor cells and reduce the risk of emergence of immune escape variants. Here, we evaluated the capacity of a polypeptide composed of optimized cryptic peptides derived from three different universal tumor antigens (TERT988Y, HER-2/neu402Y and MAGE-A248V9) to induce a polyspecific CD8 cell response both in vivo in HHD mice and in vitro in humans. A mixture of TERT988Y, HER-2/neu402Y and MAGE-A248V9 peptides failed to induce a trispecific response. In contrast, a polypeptide composed of the three peptides stimulated a trispecific immune response. Interestingly, the capacity of the polypeptide to induce a trispecific response depended on its internal organization. Six different polypeptide variants corresponding to all possible combinations of the three peptides were tested. Only one variant, named Poly-6, elicited an immune response simultaneously targeting all three peptides.