Optimization of a public neoantigen-based cancer prevention strategy - While personalized neoantigen vaccines have shown therapeutic promise, their efficacy is often impaired by immunoediting and immune suppression in established cancers. Preventive vaccination prior to cancer onset offers a compelling alternative, as shown by the success of HPV vaccines in preventing HPV-related cancers. However, effective prevention vaccines for most non-viral cancers remain elusive, largely due to the challenges of identifying antigens capable of eliciting broad protection across diverse cancer types. Public neoantigens are derived from driver hotspot mutations, presented by common major histocompatibility complex (MHC) alleles, and capable of eliciting dynamic T-cell response, making them promising targets for scalable, off-the-shelf vaccines. However, their subtle differences from self-peptides make them less immunogenic. Thus, developing a novel platform to induce strong, durable cell mediate immunity, and testing the platform in a relevant model system before human trials are essential. Commonly used rodent models for cancer prevention do not fully capture the heterogeneity, complexity, spontaneity, and often prolonged course of tumorigenesis in humans, complicating translational efforts. We propose to leverage pet dogs, particularly Golden Retriever (GR) pet dogs, as a novel alternative model system (NAMS) for cancer prevention, given their high spontaneous cancer incidence, shared driver hotspot mutations, and compatible MHC alleles with humans. We have identified 30 public neoantigen candidates, 48% of which are already validated and collectively have a potential to impact 0.41 billion people, and cloned them into an innovative, highly immunogenic parainfluenza virus 5-based self-amplifying virus-like particle (PIV5- saVLP) vaccine platform. Our central hypothesis is that vaccination with this novel platform in GRs will induce durable, protective immunity, serving as a critical translational step toward human cancer prevention. Specific aims include (1) conducting a vaccination trial in healthy GRs to assess safety, immunogenicity, and preliminary efficacy while characterizing immune correlates, and (2) identifying dog-human antigen-presentation equivalent MHC alleles and functionally equivalent, neoantigen-specific T cells to facilitate future clinical translation. This project will provide key insights into public neoantigen immunogenicity and cancer-preventive immunity in a relevant large-animal model, while establishing a blueprint for successful future human translation.
