Development of Rationally Designed Cancer Vaccines Using Protein-like Polymers (PLPs)

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PROJECT SUMMARY The utilization of tumor antigens, which are antigenic peptides expressed in cancer cells as a result of random somatic mutations, for the development of patient-specific therapeutic cancer vaccines has been an area of intense interest. However, significant challenges remain in safely and efficiently delivering subunit vaccine components for the elicitation of robust antitumor immune responses. To overcome these challenges, this proposal utilizes a new methodology for protecting active peptides from proteolysis for the sustained delivery of tumor antigens in conjunction with immunomodulatory compounds as rationally designed cancer vaccines. This approach packages peptides together as high-density brush polymers, which results in the introduction of unique characteristics with significant advantages over conventional attempts to utilize peptides as therapeutics. These include increased resistance to proteolysis and improved pharmacokinetic profiles, while maintaining strong bioactivity and cell uptake. This peptide packaging method is termed Protein-Like Polymers (PLPs) due to its globular, peptide-based structure assembled around a hydrophobic synthetic polymer core, displaying active amino acids for recognition and function in a sequence-controlled manner. PLPs are modular in terms of payload, able to be conjugated with defined proportions of peptides, small molecules, and nucleic acids. Further modifications of PLPs can confer additional properties including tissue targeting, site-specific cargo release, and changes in packing density. The PLP nanoplatform demonstrates that compounds arranged in unique 3- dimensional structures exhibit properties exclusive to that configuration, providing new avenues for biomolecule delivery. For this proposal, PLPs will be used to overcome inherent difficulties associated with utilizing tumor antigens as cancer vaccines, namely by preventing their degradation, enabling targeted delivery, and allowing proportion-defined multivalent display of dissimilar antigens with immunostimulatory compounds.