Polyionic Papillomavirus-like Particles (VLP) for the Treatment of HPV+ oropharyngeal squamous cell carcinomas (OPCs)

用于治疗 HPV 口咽鳞状细胞癌 (OPC) 的聚离子乳头瘤病毒样颗粒 (VLP)

• 批准号: 9463808
• 负责人: JOSHUA WEIYUAN WANG
• 金额: $ 30万
• 依托单位: PATHOVAX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9463808
• 关键词: Address; Adjuvant; Adverse effects; Amino Acids; Antibodies; Antigens; Area; Bacteriophages; Biological; Bovine Papillomavirus; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; Cancer Vaccines; Capsid Proteins; Cells; Cervarix; Chemicals; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Cysteine; DNA Vaccines; Data; Development; Eligibility Determination; Ensure; Epitopes; FDA approved; Failure; 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; Immunosuppression; Immunotherapy; Incidence; Individual; Infectious Agent; Infusion procedures; Legal patent; Length; Letters; Link; Liposomes; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Methods; Modeling; Mus; Mutagens; Nanotechnology; Oropharyngeal Neoplasms; Oropharyngeal Squamous Cell Carcinoma; Papillomaviridae; Papillomavirus; Pathway interactions; Patients; Peptides; Pharmacologic Substance; Phase; Polyglutamic Acid; Polymers; Process; Proteins; Recruitment Activity; Risk; Risk Factors; Safety; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Surface; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Translations; Treatment Efficacy; Treatment Protocols; Tumor Antigens; Universities; Vaccination; Vaccines; Viral; Viral Vector; Virus-like particle; Wild Type Mouse; Xenograft procedure; antitumor effect; base; cancer epidemiology; cancer immunotherapy; clinical efficacy; clinical practice; clinically relevant; cross reactivity; cytotoxic; design; effective therapy; efficacy study; exhaustion; immunogenic; immunogenicity; improved; improved outcome; interest; killings; malignant oropharynx neoplasm; manufacturing process; meetings; mouse model; nanoparticle; new technology; novel; particle; plasmid DNA; polyarginine; polyion; pre-clinical; prototype; response; sedimentation velocity; subcutaneous; success; tobacco exposure; tumor; tumor microenvironment; vaccine development

The broader impact/commercial potential of PathoVax’s 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. PathoVax’s 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.

PathoVax的STTR第一阶段提案的更广泛的影响/商业潜力是改善 利用结合免疫原性嵌合病毒样颗粒的疫苗制剂的癌症免疫治疗 （cVLP）疫苗与FDA批准的免疫检查点抑制剂。PathoVax建议开发这种 治疗人乳头瘤病毒（HPV）相关癌症的技术。然而，癌症疫苗， 一般来说，在临床试验中表现出较差的疗效。我们认为，他们的失败反映了 癌症疫苗技术。质粒DNA疫苗在人体中的免疫原性较弱。活病毒载体 存在固有的问题，包括交叉反应性免疫和免疫受损的安全风险 个体单独的肽是免疫原性差的，并且是增强细胞免疫的可用佐剂 反应的效力有限。克服免疫接种面临的挑战并改善免疫接种 为了提高免疫疗法的治疗效果，PathoVax开发了一种新的技术， 应答PathoVax的专利VLP与检查点抑制剂配方利用了当前的范例 由此癌症疫苗在与检查点抑制结合时可能是最有效的。有 使用乳头瘤病毒VLP的安全先例（Gardasil和Cervarix）。我们的VLP技术可以 肿瘤内募集免疫细胞以使曾经“非发炎”的非容许肿瘤对这两种物质敏感 细胞毒性杀伤和检查点抑制剂。在初步研究中，我们已经表明，我们的cVLPs显示了 HPV 16 E7 aa 49 -57 Kb限制性表位诱导稳健的CD 8 + T细胞应答并显示出治疗性 在TC-1 C57 BL/6小鼠肿瘤模型中的有效性。转化为临床将需要抗原跨越 全长HPV 16 E6和E7蛋白。本第一阶段提案的技术目标主要集中在 重新配制我们的疫苗以包含这些E6/E7抗原，并表征我们的cVLP以确保产品 在转化为临床时具有一致的特征和生物活性（Aim 1）。我们将利用这个 最终制剂，以评估我们表征的制剂在临床相关的小鼠模型中的功效。 HPV+ OPC（目的2）。成功实施这一建议将为进一步加强 在II期STTR中进行表征和GLP疗效研究，以创建稳健的临床前数据包， IND前FDA讨论。HPV-OPSCC领域的积极成果（全球价值8500万美元）也将 鼓励将该技术作为一个平台扩展到其他癌症和传染病。重要的是 提供了一个途径，以吸引机构投资者或制药合作伙伴的支持以外的 STTR/SBIR过程。