Development of a dendritic cell-targeted vaccine strategy using proximity-induced conjugation

Traditional cancer vaccines that utilize peptides or proteins often exhibit limited efficacy as a result of mutations in cancer antigenic epitopes, also known as antigenic drift, which reduce the ability of traditional vaccines to target tumor antigens and elicit robust immune response.

To address these challenges, we propose an innovative and universal strategy for dendritic cell (DC)-targeted neoepitope delivery via proximity-induced conjugation (PIC). This approach enables the site-specific crosslink of a broad spectrum of neoepitopes tailored to diverse cancer types, thereby increasing both vaccine flexibility and applicability. The PIC method involves the use of recombinant Fc-affinity peptides that are modified with two distinct unnatural amino acids: the photoreactive amino acid p-benzoyl-L-phenylalanine (pBPA) and the bioorthogonal reactive amino acid 4-fluorophenyl carbamate lysine (FPheK). These modified peptides allow for the precise conjugation of neoepitopes through ultraviolet (UV) irradiation or mild incubation, thereby achieving controlled antigen coupling.

Through optimization of this strategy, we observed a substantial increase in DCs mediated antigen uptake and processing, leading to enhanced T cell activation, a robust cytotoxic immune response, and significant improvements in antitumor efficacy. Moreover, the DC-targeted vaccine exhibited promising synergistic effects with an immune checkpoint inhibitor (ICI), resulting in a marked reduction in tumor growth and prolonged survival in preclinical models.

These findings underscore the potential of the PIC-based DC-targeted vaccine system to augment the immunogenicity, versatility, and therapeutic efficacy of cancer vaccines. This strategy offers a compelling solution to the challenges posed by antigenic drift and mutation, thereby improving clinical outcomes across a broad range of cancers.