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: 8138988
• 负责人: Frank R. Jones
• 金额: $ 16.34万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138988
• 关键词: AIDS therapy; Adenoviruses; Adverse effects; Agonist; Animals; Anti-Retroviral Agents; Antigen Targeting; Antigen-Presenting Cells; Antigens; Cancer Model; Carcinoembryonic Antigen; Cells; Clinical Data; Combined Modality Therapy; DNA-Directed DNA Polymerase; Data; Disease; ERBB2 gene; Fas-associated phosphatase-1; Generations; Genes; HIV; HIV Antigens; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Human papilloma virus infection; Immune; Immune Targeting; Immune response; Immunity; Immunization; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Malignant Neoplasms; Mediating; Monitor; Monkeys; Morbidity - disease rate; Mus; Oncogene Proteins; Oral; Oropharyngeal; Pathogenesis; Patients; Pharmaceutical Preparations; Plaque Assay; Prevalence; Proteins; Recombinants; Regimen; Reporting; Risk; Role; Serotyping; Technology; Telomerase; Testing; Therapeutic; Time; TimeLine; Toll-like receptors; Tonsil; Transfection; Tumor Antigens; United States; Vaccines; Viral Vector; Western Blotting; base; clinically relevant; design; immunogenicity; in vivo; malignant breast neoplasm; malignant oropharynx neoplasm; malignant tonsil neoplasm; mortality; non-oncogenic; novel; novel vaccines; pandemic disease; pre-clinical; prevent; research study; response; therapeutic vaccine; tumor; tumor growth; tumor progression; vaccine development; vector; vector vaccine; vector-induced; viral DNA; virus related cancer

DESCRIPTION (provided by applicant): The objective of this project is to develop a therapeutic strategy for H|V-associated malignancy based on the role of HPV in the pathogenesis. HPV related cancers express the E6/E7 oncoproteins of HPV that are ideal targets for immune inducing vaccines. We will develop a vaccine based upon a novel adenovirus serotype-S vector (Ads) platform with unique and additional deletions of the viral DNA polymerase and the pre- terminal protein in the early gene 2b (E2b) region (Ads [E1-, E2b-]). In studies employing HIV antigens, we reported that the new Ad5 [E1-, E2b-]-HlV vector vaccine was superior to a current Ads [E1-]-H|V vector vaccine (containing deletion in the early gene 1 (E1) region) when used to induce CMI responses in a multiple immunization regimen. Significant antigen specific CMI responses were induced in mice and monkeys despite the presence of pre-existing AdS immunity. We will construct and produce an AdS [E1-, E2b-] vector vaccine that contains the HPV oncoproteins E6/E7 with non-oncogenic function. This new recombinant adenovirus will induce immune responses by expressing the modified HPV-E6/E7 antigens after direct transfection of antigen presenting cells. We will evaluate this in combination with a toll-like receptor agonist (TLRa) designed to enhance immune responses induced by the vaccine. Our pre-clinical data indicate that the AdS [E1-, E2b-] vec*or induces robust CMI responses against tumor associated antigen [fAA), even in the presence of pre- existing AdS immunity. In a murine cancer model employing the carcinoembryonic antigen (CEA) gene insert, tl.g -CEA immunogenicity and in vivo anti-tumor effects of repeated immunizations with i new AdS [E1-, E2b-l- GEA were compared to those observed with a current generation Ads tE1-l-CEA. These AdS vectors were tested in a clinically relevant AdS immune setting. We observed that AdS immune mice immunized multiple times with AdS [E1-, E2b-]-CEA induced CEA-specific CMI responses that were significantly increased over those detected in AdS immune mice immunized multiple times with a current generation AdS tE1-l-CEA. Ads immune mice bearing CEA expressing tumors that were treated with AdS [E1-, E2b-J-CEA had an increased anti-tumor response as compared to AdS [E1-I-CEA treated mice. These results demonstrate that AdS [E1-, Ezb-l-CEA can induce CMI immune responses that result in tumor growth inhibition despite the presence of pre-existing AdS immunity. We have also utilized the Ads [E1-, Ezb-] vector platform expressing the TAA HER2lneu as a breast cancer immunotherapeutic agent. Ads [E1-, E2b-l-HERZlneu induced potent CMI against HER2/neu and significantly inhibited progression of established tumors in Ad5 immune mice. These data demonstrate that in vivo delivery of Ad5 [E1-, E2b-] vectors expressing TM can induce anti-TAA immunity and inhibit progression of tumors in AdS immune animals. PUBLIC HEALTH RELEVANCE: In this study, we will develop a new adenoviral based drug (AdS [E1-, E2b-I-HPV-E6/7) to treat HtV+ patients with HPv-associated oropharyngeal and tonsillar ,ncers. The treatment platform is needed to overcome pre-existing AdS immunity that has prevented the widespread use of this type of technology.

描述（由申请人提供）：本项目的目的是开发一种治疗H|基于HPV在发病机制中的作用的V相关恶性肿瘤。HPV相关的癌症表达HPV的E6/E7癌蛋白，其是免疫诱导疫苗的理想靶标。我们将开发一种基于新型腺病毒S型载体（Ads）平台的疫苗，该平台具有病毒DNA聚合酶和早期基因2b（E2 b）区域中的前末端蛋白的独特和额外缺失（Ads [E1-，E2 b-]）。在使用HIV抗原的研究中，我们报告了新的Ad 5 [E1-，E2 b-]-HlV载体疫苗上级当前的Ad [E1-]-H| V载体疫苗（包含早期基因1（E1）区域的缺失），用于在多次免疫方案中诱导CMI应答。尽管存在预先存在的AdS免疫，但在小鼠和猴中诱导了显著的抗原特异性CMI应答。我们将构建并生产一种含有非致癌功能的HPV癌蛋白E6/E7的AdS [E1-，E2 b-]载体疫苗。这种新型重组腺病毒将通过直接转染抗原呈递细胞后表达修饰的HPV-E6/E7抗原来诱导免疫应答。我们将评估这一点与toll样受体激动剂（TLRa）的组合，旨在增强疫苗诱导的免疫反应。我们的临床前数据表明，AdS [El-，E2 b-] vec* 或诱导针对肿瘤相关抗原[fAA）的稳健CMI应答，即使在预先存在的AdS免疫的情况下。在使用癌胚抗原（CEA）基因插入物的鼠癌症模型中，将用新AdS [E1-，E2 b-1- GEA]重复免疫的t1-g-CEA免疫原性和体内抗肿瘤作用与用当前一代Ads tE 1-l-CEA观察到的那些进行比较。在临床相关的AdS免疫环境中测试这些AdS载体。我们观察到，用AdS [E1-，E2 b-]-CEA多次免疫的AdS免疫小鼠诱导的CEA特异性CMI应答显著高于用当前一代AdS tE 1-l-CEA多次免疫的AdS免疫小鼠中检测到的应答。与AdS [E1- 1]-CEA处理的小鼠相比，用AdS [E1- 1]-CEA处理的携带CEA表达肿瘤的Ads免疫小鼠具有增加的抗肿瘤应答。这些结果表明，AdS [El-，Ezb-l-CEA]可以诱导CMI免疫应答，尽管存在预先存在的AdS免疫，但所述CMI免疫应答导致肿瘤生长抑制。我们还利用表达TAA HER 2lneu的Ads [El-，Ezb-]载体平台作为乳腺癌免疫抑制剂。Ads [El-，E2 b-1-HERZlneu]诱导针对HER 2/neu的有效CMI，并显著抑制Ad 5免疫小鼠中已建立肿瘤的进展。这些数据表明，表达TM的Ad 5 [E1-，E2 b-]载体的体内递送可以诱导抗TAA免疫并抑制AdS免疫动物中的肿瘤进展。 公共卫生关系：在本研究中，我们将开发一种新的基于腺病毒的药物（AdS [E1-，E2 b-I-HPV-E6/7）来治疗患有HPV相关口咽和扁桃体癌的HtV+患者。治疗平台需要克服预先存在的AdS免疫力，这种免疫力阻止了这种技术的广泛使用。