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）感染的治疗是一项未满足的主要医疗需求。重要的是，获得许可的 HPV 疫苗无法清除现有感染，而且现在有多种 FDA 批准的检测方法可以检测高风险 HPV DNA，特别是 HPV16。随着这些 HPV DNA 检测的广泛实施，大量的感染患者正在被识别出来。目前，持续存在的 HPV16+ 患者未接受治疗，但 对他们进行跟踪，直到他们发展为癌前病变，然后接受手术或消融干预，费用高昂且副作用巨大。我们的总体目标是开发一种治疗性疫苗来消除持续的 HPV16 感染。治疗性 HPV 疫苗不需要抗体，而是需要有效的细胞毒性 T 细胞免疫反应来控制慢性 HPV 感染和 HPV 相关疾病。 HPV 早期蛋白 E6 和 E7 在所有 HPV 感染的细胞中专性表达，在正常细胞中不表达，并且是“非自身”抗原。因此，虽然 E6 和 E7 是治疗性 HPV 疫苗接种的合理目标，但它们的免疫原性较弱，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。我们之前使用裸 DNA 疫苗通过与结核分枝杆菌热休克蛋白 70 (HSP70) 融合，显着增强 HPV16 E7 的 MHC I 类呈递。这种联系将 E7 特异性 CD8+ T 细胞免疫反应增强了至少 50 倍，并对接种疫苗的小鼠中表达 HPV16 E7 的细胞产生了有效的治疗效果。这些数据导致了针对 HPV16+ 患者的 I 期临床试验，证明 E7HSP70 DNA 疫苗免疫可诱导患者产生 E7 特异性 CD8+ T 细胞反应。 TA-HPV 是经过改造的痘苗病毒，可表达 HPV16 和 HPV18 的 E6 和 E7 基因。对近百名 HPV16+ 宫颈癌和肛门生殖器肿瘤患者进行 TA-HPV 皮肤注射，未能产生明确的临床反应。重要的是，虽然用 E7HSP70 DNA 疫苗对小鼠进行初免，然后用表达 HPV E7 的重组痘苗进行皮肤加强，增强了 E7 特异性 CD8+ T 细胞反应，但我们最近证明，用表达 E7 的痘苗进行病灶内加强比皮肤加强或免疫加强更有效。病灶内单独使用 E7 牛痘。我们假设，用 E7HSP70 DNA 疫苗引发，然后病灶内注射 TA-HPV 痘苗（也表达 HPV16 E7），将通过结合优先痘苗复制和细胞杀伤作用，对持续性 HPV 感染产生有效的治疗效果。 HPV 抗原特异性 CD8+ T 细胞介导的免疫反应增强，吸引到病变部位。因此，我们将使用小鼠阴道持续感染 HPV16 的新模型来测试临床级 HPV DNA 疫苗和病灶内注射 HPV 重组痘苗是否会触发免疫清除。这些临床前研究将推动未来由 Papivax 驱动的治疗性疫苗临床试验，以消除持续性 HPV 感染。