Therapeutic vaccination against genital HPV infection

针对生殖器 HPV 感染的治疗性疫苗接种

• 批准号: 8522917
• 负责人: Yung-Nien Chang
• 金额: $ 28.82万
• 依托单位: PAPIVAX, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-10 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522917
• 关键词: Adverse effects; Anogenital cancer; Antigens; Anus; Autoantigens; Binding; CD8B1 gene; Cells; Cervical; Cervix Uteri; Chronic; Clinical; Clinical Trials; Cutaneous; Cutaneous Administration; Cytopathology; Cytotoxic T-Lymphocytes; DNA; DNA Vaccines; Data; Detox; Development; Disease; Engineering; Epithelial; Excision; FDA approved; Foundations; Future; Genes; Genital Human Papilloma Virus Infection; Goals; HPV-High Risk; Head and Neck Cancer; Heat-Shock Proteins 70; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; Immune Tolerance; Immune response; Immunity; Immunization; Infection; Injection of therapeutic agent; Intellectual Property; Intervention; Intraepithelial Neoplasia; Intralesional Injections; L1 viral capsid protein; Lead; Lesion; Licensing; MHC Class I Genes; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Medical; Modeling; Mus; Mutate; Mycobacterium tuberculosis; Neoplasms; Normal Cell; Oncogenic; Operative Surgical Procedures; Patients; Phase I Clinical Trials; Pre-Clinical Model; Preventive; Proteins; Psychosocial Stress; Recombinants; Recurrence; Retinoblastoma Protein; Rights; Secondary Immunization; Smallpox Vaccine; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic antibodies; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Vaccinia; Vaccinia virus; Vaccinium; Vagina; Viral; Woman; base; cell killing; cell mediated immune response; cell transformation; cervicovaginal; cost; high risk; immortalized cell; immune clearance; immunogenic; intraepithelial; mouse model; neutralizing antibody; novel; preclinical study; prevent; public health relevance; response; screening; standard of care; therapeutic target; therapeutic vaccine; tumor

DESCRIPTION (provided by applicant): Treatment of Human papillomavirus (HPV) infections is a major unmet medical need. Importantly, the licensed HPV vaccines are not able to clear existing infections, and there are now multiple FDA-approved tests to detect high risk HPV DNA, and specifically HPV16. As these HPV DNA tests are widely implemented, large numbers of infected patients are being identified. Currently persistently HPV16+ patients are not treated, but are followed until they develop pre-cancer and then undergo a surgical or ablative intervention with significant costs and side effects. Our overall goal is to develop a therapeutic vaccine to eliminate persistent HPV16 infections. Rather than antibodies, therapeutic HPV vaccines require a potent cytotoxic T cell immune response to control chronic HPV infections and HPV-associated disease. The HPV early proteins E6 and E7 are obligately expressed in all HPV infected cells, absent from normal cells and are 'non-self' antigens. Thus while E6 and E7 are the logical targets for therapeutic HPV vaccination, nevertheless they are weakly immunogenic and require Papivax's novel immunostimulatory technology to generate potent cytotoxic T cell immunity. We have previously utilized a naked DNA vaccine to significantly enhance MHC class I presentation of HPV16 E7 by its fusion to the Mycobacterium tuberculosis heat shock protein 70 (HSP70). This linkage augmented the E7-specific CD8+ T cell immune responses at least 50-fold and led to potent therapeutic effects against HPV16 E7-expressing cells in vaccinated mice. These data led to a phase I clinical trial in HPV16+ patients which demonstrated that immunization with E7HSP70 DNA vaccine induces an E7-specific CD8+ T cell response in patients. TA-HPV is vaccinia virus engineered to express the E6 and E7 genes from HPV16 and HPV18. Cutaneous administration of TA-HPV to nearly a hundred patients with HPV16+ cervical cancer and anogenital neoplasias failed to produce a clear clinical response. Importantly, while priming of mice with the E7HSP70 DNA vaccine followed by cutaneous boosting with recombinant vaccinia expressing HPV E7 enhanced E7-specific CD8+ T cell responses, we recently demonstrated that intralesional boosting with E7- expressing vaccinia was far more effective than either cutaneous boosting or intralesional E7-vaccinia alone. We hypothesize that priming with the E7HSP70 DNA vaccine followed by intralesional injection of TA-HPV vaccinia (which also expresses HPV16 E7) will generate potent therapeutic effects against persistent HPV infection by combining preferential vaccinia replication and cell killing in the lesion with boosting of HPV antigen-specific CD8+ T cell mediated immune responses attracted to the lesion. Thus, we will test whether combining clinical grade HPV DNA vaccine and intra-lesional administration of HPV recombinant vaccinia triggers immune clearance using a new model of persistent HPV16 infection in the mouse vagina. These preclinical studies will drive future Papivax-driven clinical trials of therapeutic vaccines to eliminate persistent HPV infections.

描述（由申请人提供）：人乳头瘤病毒（HPV）感染的治疗是主要的未满足医疗需求。重要的是，获得许可的HPV疫苗无法清除现有的感染，现在有多次FDA批准的测试可检测高风险HPV DNA，特别是HPV16。由于这些HPV DNA测试被广泛实施，因此正在确定大量感染患者。目前持续使用HPV16+患者未接受治疗，但 紧随其后，直到他们发展前癌症，然后进行外科手术或消融性干预，并具有巨大的成本和副​​作用。我们的总体目标是开发一种治疗性疫苗，以消除持续的HPV16感染。治疗性HPV疫苗而不是抗体，需要有效的细胞毒性T细胞免疫反应，以控制慢性HPV感染和HPV相关疾病。 HPV早期蛋白E6和E7在所有HPV感染的细胞中均可表达，正常细胞不存在，并且是“非自身”抗原。因此，尽管E6和E7是治疗性HPV疫苗接种的逻辑靶标，但它们是弱免疫原性的，需要Papivax的新型免疫刺激技术来产生有效的细胞毒性T细胞免疫。我们以前曾使用裸DNA疫苗来显着增强HPV16 E7的MHC I类表现，并通过其融合到结核分枝杆菌热休克蛋白70（HSP70）。这种连锁增强了E7特异性CD8+ T细胞免疫反应至少50倍，并在接种疫苗的小鼠中对表达HPV16 E7的细胞产生了有效的治疗作用。这些数据导致了HPV16+患者的I期临床试验，该试验表明，用E7HSP70 DNA疫苗免疫会诱导患者的E7特异性CD8+ T细胞反应。 TA-HPV是疫苗病毒，该病毒设计为从HPV16和HPV18表达E6和E7基因。向近一百名HPV16+宫颈癌和肛门生态性肿瘤的患者使用皮肤TA-HPV未能产生明确的临床反应。重要的是，虽然用E7HSP70 DNA疫苗启动小鼠，然后用表达HPV E7增强的重组疫苗增强皮肤的E7特异性CD8+ T细胞反应，但最近证明，内部内部的增强效率是E7-表达疫苗的效果比两性boost beost或Intraliss e7-boost e7-a-boost e7-a-nimia a7-boost e7-a7-nimia a7-nimia。我们假设使用E7HSP70 DNA疫苗启动，然后在遗传内注射TA-HPV疫苗（也表达HPV16 E7）将通过结合优先效果复制和细胞杀死持续的HPV感染而产生有效的治疗作用。 促进HPV抗原特异性CD8+ T细胞介导的免疫反应的病变吸引了病变。因此，我们将测试使用小鼠阴道中持续的HPV16感染的新模型，将HPV重组疫苗的临床级HPV DNA疫苗和HPV重组疫苗的治疗施用是否触发免疫清除率。这些临床前研究将推动未来由Papivax驱动的治疗疫苗临床试验，以消除持续的HPV感染。