The broader impact/commercial potential of PathoVaxs STTR phase I proposal is to improve outcomes of cancer immuno-therapy, utilizing a vaccine formulation combining an immunogenic chimeric virus-like particle (cVLP) vaccine with FDA-approved immune check-point inhibitors. PathoVax proposes to develop this technology for treatment of human papillomavirus (HPV)-associated cancers. However, cancer vaccines have, in general, shown poor efficacy in clinical trials. We contend that their failure reflects inherent deficiencies in cancer vaccine technologies. Plasmid DNA vaccines are weakly immunogenic in humans. Live viral vectors possess inherent concerns including cross-reactive immunity and safety risks for immune compromised individuals. Peptides alone are poorly immunogenic and available adjuvants to enhance cellular immune responses have limited efficacy. To overcome the challenges faced by immunization and improve the treatment efficacy of immunotherapy, PathoVax has developed a novel technology for inducing T cell responses. PathoVaxs patented VLP with checkpoint inhibitors formulation leverages the current paradigm whereby cancer vaccines are likely to be most effective when combined with checkpoint inhibition. There is safety precedent for use of papillomavirus VLPs (Gardasil and Cervarix). Our VLP technology can prime the intratumoral recruitment of immune cells to sensitize once non-inflamed non-permissive tumors to both cytotoxic-killing and checkpoint inhibitors. In preliminary studies, we have shown that our cVLPs displaying the HPV 16 E7aa49-57 Kb-restricted epitope induced robust CD8+ T cell responses and demonstrated therapeutic efficacy in the TC-1 C57BL/6 mouse tumor model. Translation into the clinic will require antigens spanning the full length of HPV16 E6 and E7 proteins. Technical objectives of this Phase I proposal are focused on reformulating our vaccine to encompass these E6/E7 antigens, and characterize our cVLP to ensure a product with consistent features and biological activity upon translation into the clinic (Aim1). We will then utilize this final formulation to assess the efficacy of our characterized formulation in a clinically relevant mouse model of HPV+ OPC (aim 2). Successful implementation of this proposal will be the foundation for additional characterization and GLP efficacy studies in a Phase II STTR to create a robust pre-clinical data package for pre-IND FDA discussions. Positive results in the area of HPV-OPSCC (valued at US$85M globally) will also encourage extension of the technology as a platform to other cancers and infectious agents. Importantly, it provides a pathway to attract institutional investors or pharmaceutical partners for support beyond the STTR/SBIR process.
Public Health Relevance Statement: This proposal aims to develop PathoVaxs polyionic papillomavirus chimeric virus-like particle (cVLP) combined with immune-checkpoint inhibitors for Human Papillomavirus (HPV)- associated oropharyngeal (OPC) cancers. Our academic partners proof of concept studies have shown positive vaccine therapeutic effects against viral-associated tumors, and we have received feedback from a potentially interested pharmaceutical collaborator on what further studies we would need to perform to initiate potentially a collaboration beyond this STTR. This includes characterization studies of our cVLP vaccine utilizing multiple peptides and testing this in combination with checkpoint inhibitors in a relevant clinical model emulating HPV+ OPCs.
Project Terms: Address; Adjuvant; Adverse effects; Amino Acids; Antibodies; Antigens; antitumor effect; Area; Bacteriophages; base; Biological; Bovine Papillomavirus; C57BL/6 Mouse; cancer epidemiology; cancer immunotherapy; Cancer Vaccines; Capsid Proteins; CD8-Positive T-Lymphocytes; Cells; Cervarix; Chemicals; Clinic; Clinical; Clinical Data; clinical efficacy; clinical practice; Clinical Trials; clinically relevant; Collaborations; cross reactivity; Cysteine; cytotoxic; Data; design; Development; DNA Vaccines; effective therapy; efficacy study; Eligibility Determination; Ensure; Epitopes; exhaustion; Failure; FDA approved; Feedback; Formulation; Foundations; Gardasil; Genetic Engineering; Glycolates; Goals; Haplotypes; Head and Neck Cancer; High Pressure Liquid Chromatography; Human; Human Papillomavirus; Human papillomavirus 16; Human papillomavirus 6; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunization; immunogenic; immunogenicity; Immunotherapy; improved; improved outcome; Incidence; Individual; Infectious Agent; Infusion procedures; interest; Killings; Legal patent; Length; Letters; Link; Liposomes; Malignant neoplasm of cervix uteri; Malignant Neoplasms; malignant oropharynx neoplasm; manufacturing process; Mediating; meetings; Methods; Modeling; mouse model; Mus; Mutagens; nanoparticle; Nanotechnology; Natural immunosuppression; new technology; novel; Oropharyngeal Neoplasms; Oropharyngeal Squamous Cell Carcinoma; Papillomaviridae; Papillomavirus; particle; Pathway interactions; Patients; Peptides; Pharmacologic Substance; Phase; plasmid DNA; polyarginine; Polyglutamic Acid; polyion; Polymers; pre-clinical; Process; Proteins; prototype; Recruitment Activity; response; Risk; Risk Factors; Safety; sedimentation velocity; Small Business Innovation Research Grant; Small Business Technology Transfer Research; subcutaneous; success; Surface; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; tobacco exposure; Toxic effect; Translations; Treatment Efficacy; Treatment Protocols; tumor; Tumor Antigens; tumor microenvironment; Universities; Vaccination; vaccine development; Vaccines; Viral; Viral Vector; Virus-like particle; Wild Type Mouse; Xenograft procedure
