Therapeutic Cancer Vaccination with Immunopeptidomics-Discovered Antigens Confers Protective Antitumor Efficacy

Abstract

Knowledge of clinically targetable tumor antigens is becoming vital for broader design and utility of therapeutic cancer vaccines. This information is obtained reliably by directly interrogating the MHC-I presented peptide ligands, the immunopeptidome, with state-of-the-art mass spectrometry. Our manuscript describes direct identification of novel tumor antigens for an aggressive triple-negative breast cancer model. Immunopeptidome profiling revealed 2481 unique antigens, among them a novel ERV antigen originating from an endogenous retrovirus element. The clinical benefit and tumor control potential of the identified tumor antigens and ERV antigen were studied in a preclinical model using two vaccine platforms and therapeutic settings. Prominent control of established tumors was achieved using an oncolytic adenovirus platform designed for flexible and specific tumor targeting, namely PeptiCRAd. Our study presents a pipeline integrating immunopeptidome analysis-driven antigen discovery with a therapeutic cancer vaccine platform for improved personalized oncolytic immunotherapy.

Development of mesothelioma-specific oncolytic vaccine exploiting immunopeptidomic analysis of murine and human tumors

“…Specifically, PeptiCRAd combines the immunogenicity of the adenovirus with the tumor specificity conferred by the peptides, eliciting a strong anti-tumor immune response. In this study, we showed that PeptiCRAd technology was successfully used to treat the established mesothelioma tumor model in vivo, providing a proof-of-concept that peptides identified by immunopeptidomics can be used for the development of cancer vaccines, as we have also previously demonstrated for other tumor models (14,16).…”

“…PeptiCRAd complexes were prepared as previously described elsewhere (13)(14)(15)(16). Briefly, complexes were formed by mixing Ad5/3-D24 virus and peptides with a poly K tail (in PBS) at a ratio of 20μg of peptides per 1x109 VP per mouse in minimum volume.…”

“…PeptiCRAd is a vaccine platform consisting of an oncolytic adenovirus (OAd) whose capsid is decorated, via electrostatic interaction, with tumor-derived peptides elongated at the N-terminus with a poly-lysine tail (poly-K peptides). This platform has been successfully employed to generate multiple proofs-of-concepts for the treatment of different murine tumor models (13)(14)(15)(16). To produce PeptiCRAd, a poly-K version of the previously selected peptides was synthesized.…”

“…This technology consists of an oncolytic adenovirus (OAd) coated with tumor-specific peptides, which integrates viral immunogenicity with the cancer specificity of the peptides. PeptiCRAd already showed extensive efficacy in vivo in the context of different tumor types (13)(14)(15)(16).…”

Peptides-Coated Oncolytic Vaccines for Cancer Personalized Medicine

“…PeptiCRAd consists of an OAd coated through electrostatic interactions with positively charged MHC-I restricted tumor peptides (poly-lysine tail-peptides) ( 26 ). The reaction requires only 15 minutes and several studies have shown its anti-tumor efficacy and immunological modulation in different contexts and tumor models such as murine triple-negative breast cancer ( 34 ), as a cancer therapeutic platform for immunopeptidomic pipelines ( 7 , 35 ), as a tool to explore viral mimicry to tumor antigens for cancer immunotherapy ( 36 ), as a platform to exploit pre-existing immunity to pathogens for boosting anti-tumoral CD8 T cell response ( 37 ) or to decorate with tumor peptides OAd encoding immunostimulatory molecules ( 38 ). However, we have never compared our cancer vaccine platform with traditional approaches in the field such as OAd genetically modified to encode TAs.…”