Therapeutic Vaccine for HIV/HPV-associated Oropharyngeal and Tonsillar Malignanci

HIV/HPV 相关口咽和扁桃体恶性肿瘤的治疗疫苗

• 批准号: 8690818
• 负责人: Frank R. Jones
• 金额: $ 41.44万
• 依托单位: ETUBICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690818
• 关键词: AIDS therapy; Adenoviruses; Adjuvant; Agonist; Animals; Anti-Retroviral Agents; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Biological Assay; Cancer Model; Cells; Clinical Trials; Combined Modality Therapy; Communicable Diseases; DNA-Directed DNA Polymerase; Data; Disease; Dose; Effectiveness; Enzyme-Linked Immunosorbent Assay; FDA approved; Flow Cytometry; Gene Delivery; Genes; HIV; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Human; Human Papillomavirus; Human papilloma virus infection; Immune; Immune Targeting; Immune response; Immunity; Immunization; Immunotherapeutic agent; Immunotherapy; Incidence; Individual; Injection of therapeutic agent; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Monkeys; Morbidity - disease rate; Mus; Oncogene Proteins; Oropharyngeal; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Prevalence; Proteins; Publishing; Recombinants; Regimen; Reporting; Research; Risk; Role; Safety; Serotyping; Small Business Innovation Research Grant; Staging; Testing; Therapeutic; TimeLine; Toll-like receptors; Tonsil; Transfection; Tumor Antigens; United States; Vaccines; Viral Proteins; base; cell mediated immune response; chemotherapy; design; experience; immunogenicity; in vivo; irradiation; malignant oropharynx neoplasm; malignant tonsil neoplasm; man; mortality; non-oncogenic; novel; novel strategies; novel vaccines; pandemic disease; phase 1 study; pre-clinical; preclinical study; programs; research study; therapeutic vaccine; tumor; tumor growth; vaccine development; vector; vector vaccine; vector-induced; viral DNA; virus related cancer

DESCRIPTION (provided by applicant): The objective of this project is to further develop an immunotherapeutic strategy for HIV-associated malignancy based on the role of HPV in the pathogenesis and perform the pre-clinical experiments with a new drug which allow us to enter clinical trials to test its safety and effectiveness. HPV related cancers express the E6/E7 oncoproteins of HPV that are ideal targets for immune inducing vaccines. We developed a vaccine based upon a novel adenovirus serotype-5 vector (Ad5) platform with unique and additional deletions of the viral DNA polymerase and the pre-terminal protein in the early gene 2b (E2b) region (Ad5 [E1-, E2b-]). In studies employing infectious disease and cancer antigens, we reported that new Ad5 [E1-, E2b-] vector vaccines are superior to current Ad5 [E1-] vector vaccines (containing deletion in the early gene 1 (E1) region) when used to induce CMI responses in a multiple homologous immunization regimen. We have demonstrated that significant antigen specific CMI responses are induced in mice and monkeys despite the presence of pre- existing Ad5 immunity. Our data indicates that the new Ad5 [E1-, E2b-] vectors induces robust CMI responses against tumor associated antigens (TAA) resulting in anti-tumor activity, even in the presence of pre-existing Ad5 immunity. We have constructed and produced a modified HPV-E6/E7 gene that expresses non-oncogenic early gene 6 (E6) and early gene 7 (E7) HPV proteins. We have incorporated this modified HPV-E6/E7 gene into the new recombinant Ad5 [E1-, E2b-] vector platform (Ad5 [E1-, E2b-]-HPV-E6/E7) to be used as an immunotherapeutic for the treatment of patients with HPV-E6/E7 expressing cancers. This recombinant platform induces immune responses by expressing the modified HPV-E6/E7 antigens after direct transfection of antigen presenting cells via injection. We evaluated this dru combination with a toll-like receptor agonist (TLRa) platform designed to enhance immune responses induced by the vector. In an Ad5 immune murine cancer model employing the modified HPV-E6/E7 gene insert, the immunogenicity and in vivo anti-tumor effects of repeated immunizations with the Ad5 [E1-, E2b-]-HPV-E6/E7 with or without the addition of Ad5 [E1-, E2b-]-TLRa were compared. Significantly higher levels of HPV-E6/E7 directed CMI activity was induced in mice immunized with Ad5 [E1-, E2b-]-HPV-E6/E7 plus Ad5 [E1-, E2b-]-TLRa as compared with mice immunized with Ad5 [E1-, E2b-]-HPV-E6/E7 alone. Importantly, mice treated by immunotherapy with Ad5 [E1-, E2b-]-HPV-E6/E7 with or without the addition of Ad5 [E1-, E2b-]-TLRa experienced large reductions in tumor growth as compared with control mice injected with Ad5 [E1-, E2b-]-null (empty vector). These results indicate that immunotherapy of HPV-E6/E7 expressing tumors using the new Ad5 [E1-, E2b-]-HPV-E6/E7 induces potent anti-tumor activity. Our previous research data also indicates that this new immunotherapeutic drug may be used in conjunction with chemotherapy/irradiation treatment to induce effective anti-tumor activity. The studies in the present pre-clinical program will allow us to advance manufacturing approaches and acquire data that will allow us to advance to FDA approved clinical trials

描述（由申请人提供）：该项目的目的是基于HPV在发病机制中的作用，进一步开发针对HIV相关恶性肿瘤的免疫治疗策略，并使用新药进行临床前实验，使我们能够进入临床试验以测试其安全性和有效性。 HPV 相关癌症表达 HPV 的 E6/E7 癌蛋白，它们是免疫诱导疫苗的理想靶标。我们开发了一种基于新型腺病毒血清型 5 载体 (Ad5) 平台的疫苗，该平台独特且额外删除了早期基因 2b (E2b) 区域中的病毒 DNA 聚合酶和前末端蛋白 (Ad5 [E1-, E2b- ]）。在采用传染病和癌症抗原的研究中，我们报告说，当用于预防感染时，新的 Ad5 [E1-, E2b-] 载体疫苗优于现有的 Ad5 [E1-] 载体疫苗（包含早期基因 1 (E1) 区域的缺失）。在多重同源免疫方案中诱导 CMI 反应。我们已经证明，尽管存在预先存在的 Ad5 免疫力，但在小鼠和猴子中仍能诱导显着的抗原特异性 CMI 反应。我们的数据表明，新的 Ad5 [E1-，E2b-] 载体可诱导针对肿瘤相关抗原 (TAA) 的强烈 CMI 反应，从而产生抗肿瘤活性，即使在预先存在 Ad5 免疫的情况下也是如此。我们构建并生产了修饰的 HPV-E6/E7 基因，该基因表达非致癌早期基因 6 (E6) 和早期基因 7 (E7) HPV 蛋白。我们已将此修饰的 HPV-E6/E7 基因整合到新的重组 Ad5 [E1-, E2b-] 载体平台（Ad5 [E1-, E2b-]-HPV-E6/E7）中，用作治疗的免疫疗法患有表达 HPV-E6/E7 的癌症的患者。该重组平台通过注射直接转染抗原呈递细胞后表达修饰的 HPV-E6/E7 抗原来诱导免疫反应。我们评估了这种 Dru 与 Toll 样受体激动剂 (TLRa) 平台的组合，该平台旨在增强载体诱导的免疫反应。在采用修饰的 HPV-E6/E7 基因插入的 Ad5 免疫鼠癌症模型中，使用 Ad5 [E1-, E2b-]-HPV-E6/E7 重复免疫（有或没有 HPV-E6/E7）的免疫原性和体内抗肿瘤作用比较了 Ad5 [E1-, E2b-]-TLRa 的添加。与用 Ad5 免疫的小鼠相比，用 Ad5 [E1-, E2b-]-HPV-E6/E7 加 Ad5 [E1-, E2b-]-TLRa 免疫的小鼠诱导了显着更高水平的 HPV-E6/E7 定向 CMI 活性单独[E1-，E2b-]-HPV-E6/E7。重要的是，与注射 Ad5 [E1-, E2b-]-HPV-E6/E7 的小鼠相比，添加或不添加 Ad5 [E1-, E2b-]-TLRa 的免疫疗法治疗的小鼠肿瘤生长大幅减少。 Ad5 [E1-，E2b-]-null（空向量）。这些结果表明，使用新的 Ad5 [E1-，E2b-]-HPV-E6/E7 对表达 HPV-E6/E7 的肿瘤进行免疫治疗可诱导有效的抗肿瘤活性。我们之前的研究数据还表明，这种新型免疫治疗药物可以与化疗/放疗联合使用，以诱导有效的抗肿瘤活性。当前临床前计划中的研究将使我们能够改进制造方法并获取数据，从而使我们能够进入 FDA 批准的临床试验