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: 8922494
• 负责人: Frank R. Jones
• 金额: $ 9.97万
• 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/8922494
• 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）：该项目的目的是根据HPV在发病机理中的作用，进一步制定与HIV相关的恶性肿瘤的免疫治疗策略，并使用新药物进行临床前实验，使我们能够进入临床试验以测试其安全性和有效性。 HPV相关的癌症表达HPV的E6/E7癌蛋白，这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，该平台具有独特的病毒DNA聚合酶和其他缺失，在早期基因2B（E2B）区域（AD5 [E1--，E2B-]）中的末端蛋白质和末端蛋白质。在采用传染病和癌症抗原的研究中，我们报道了新的AD5 [E1-，E2B-]载体疫苗优于当前的AD5 [E1-]载体疫苗（用于早期基因1（E1）区域中的缺失，用于诱导多种同源性免疫治疗方案中的CMI反应时。我们已经证明，尽管存在预先现有的AD5免疫力，但在小鼠和猴子中诱导了显着的抗原特异性CMI反应。我们的数据表明，即使在存在先前存在的AD5 m弱的情况下，新的AD5 [E1-，E2B-]向量也会诱导与肿瘤相关抗原（TAA）的强大CMI反应（TAA）。我们已经构建并产生了一个改良的HPV-E6/E7基因，该基因表达了非依康的早期基因6（E6）和早期基因7（E7）HPV蛋白。我们已经将这种改良的HPV-E6/E7基因纳入了新的重组AD5 [E1-，E2B-]矢量平台（AD5 [E1-，E2B-] - HPV-E6/E7），用于用于治疗HPV-E6/E7表达Cancers的HPV-E6/E7表达罐的免疫治疗。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。我们通过旨在增强载体引起的免疫反应的Toll样受体激动剂（TLRA）平台评估了这种DRU的组合。在采用修饰的HPV-E6/E7基因插入物的AD5免疫鼠类癌模型中，使用AD5 [E1-，E2B-] -HPV-E6/E7反复免疫的免疫原性和体内抗肿瘤效应，或不添加AD5 [E1-，E2B-，E2B-] - TLRA。与AD5 [E1-，E2B-] - HPV-E6/E7 Plus AD5 [E1-，E2B-] -TLRA相比，与AD5 [E1-，E2B-，E2B--，E2B--]单独使用AD5 [E1-，E2B-] - HPV-E6/E7定向CMI活性。重要的是，用AD5 [E1-，E2B-] - HPV-E6/E7通过免疫疗法治疗的小鼠，或不添加AD5 [E1-，E2B-] - TLRA与与AD5注射的对照小鼠相比，TLRA的肿瘤生长的降低大幅度降低[E1-，E2B--] - -Null（null vector）。这些结果表明，使用新的AD5 [E1-，E2B-] - HPV-E6/E7的HPV-E6/E7免疫疗法表达肿瘤，诱导有效的抗肿瘤活性。我们先前的研究数据还表明，这种新的免疫治疗药物可与化学疗法/辐照治疗结合使用以诱导有效的抗肿瘤活性。本临床前计划中的研究将使我们能够进步制造方法并获取数据，使我们能够晋升为FDA批准的临床试验