Novel Immunotherapy for the treatment of cervical cancer

治疗宫颈癌的新型免疫疗法

• 批准号: 6779667
• 负责人: Vafa Shahabi
• 金额: $ 30万
• 依托单位: ADVAXIS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-17 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779667
• 关键词: Listeria; antibiotics; attenuated microorganism; bacterial proteins; bioengineering /biomedical engineering; biotechnology; cellular immunity; cervix neoplasms; disease /disorder model; dosage; drug resistance; gene expression; genetic manipulation; human papillomavirus; laboratory mouse; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; pharmacokinetics; therapy design /development; toxicology; tumor antigens; vaccine development; vector vaccine; virus antigen; virus protein; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Despite the demonstrated efficacy of screening programs, cervical cancer continues to be a significant health issue. In 1999 alone, 12,800 women were be diagnosed with advanced cervical cancer in the U.S. and approximately 4,000 died of the disease. These women are predominantly poor and have reduced access to the health care system. Cervical cancer is primarily related to the sexual transmission of human papilloma virus (HPV). HPV has been shown to be associated with 95 percent of cervical epithelial neoplasms, and 50 percent of all-cervical cancer derives from a single strain, HPV-16. Current treatment modalities for advanced cervical cancer include chemotherapy and surgery, but morbidity and mortality remain unacceptably high. However, most cervical tumors continue to express HPV-related antigens thus providing a target for immunotherapeutic approaches. To address this challenge, Dr. Paterson's laboratory has developed a potent therapeutic vaccine vector, Listeria monocytogenes, which can target antigens to the immune system with the induction of strong cell mediated immunity. Using this approach to target the E7 antigen of HPV-16 in a mouse model, they have demonstrated that HPV-transformed macroscopic tumors can be cured. One drawback of this technology, however, has been the need to introduce antibiotic resistance genes into Listeria as a selection factor for transformation of the bacterial vector. Vectors containing these genes may not be suitable for human use because of concerns about spreading such resistance to other bacteria. Advaxis is working to commercialize these approaches. The work to be completed during this grant period will test the following hypothesis: Listeria monocytogenes, genetically engineered to express the E7 antigen in combination with certain bacterial proteins and rendered safe for human usage by attenuation and by removing antibiotic resistance genes, will show specific antitumor activity against HPV-transformed cells in vivo and ultimately in patients. The specific aims of our work during this grant period are to (1) complete the work on the engineered bacterial vector needed for the clinical trial using a strain of Listeria that does not have antibiotic resistance genes; (2) retest the re-engineered vector in the mouse model for HPV transformed cancer; (3) determine biodistribution of the therapeutic, and (4) initiate toxicology testing in the mouse. The long-term goal of the current work is to advance this therapy into and through human clinical trials. This agent could become a useful therapy for cervical cancer, either as a primary therapy or as an adjunct to standard treatments. In addition, this technology can be applied to other cancers and infectious diseases, projects that are in preclinical development.

描述（由申请人提供）：尽管筛查计划已证明有效，但宫颈癌仍然是一个重大的健康问题。仅在1999年，美国就有12，800名妇女被诊断出患有晚期宫颈癌，大约4，000人死于这种疾病。这些妇女大多数是穷人，获得保健服务的机会较少。宫颈癌主要与人乳头瘤病毒（HPV）的性传播有关。HPV已被证明与95%的宫颈上皮肿瘤有关，50%的宫颈癌来自单一菌株HPV-16。目前晚期宫颈癌的治疗方式包括化疗和手术，但发病率和死亡率仍然高得令人无法接受。然而，大多数宫颈肿瘤继续表达HPV相关抗原，从而为免疫治疗方法提供了靶点。为了应对这一挑战，Paterson博士的实验室开发了一种有效的治疗性疫苗载体，单核细胞增生李斯特菌，它可以将抗原靶向免疫系统，诱导强烈的细胞介导的免疫。使用这种方法在小鼠模型中靶向HPV-16的E7抗原，他们已经证明HPV转化的宏观肿瘤可以治愈。然而，该技术的一个缺点是需要将抗生素抗性基因引入李斯特菌中作为转化细菌载体的选择因子。含有这些基因的载体可能不适合人类使用，因为担心将这种耐药性传播给其他细菌。Advaxis正在努力将这些方法商业化。在此授权期间完成的工作将测试以下假设：李斯特菌，基因工程表达E7抗原与某些细菌蛋白质的组合，并通过减毒和去除抗生素耐药基因使人类使用安全，将在体内并最终在患者中显示对HPV转化细胞的特异性抗肿瘤活性。我们在此授权期间工作的具体目标是（1）使用不具有抗生素耐药基因的李斯特菌菌株完成临床试验所需的工程化细菌载体的工作;（2）在HPV转化癌症的小鼠模型中重新测试重新设计的载体;（3）确定治疗剂的生物分布，以及（4）在小鼠中启动毒理学测试。目前工作的长期目标是将这种疗法推进到人体临床试验中。这种药物可能成为宫颈癌的有效治疗方法，无论是作为主要治疗还是作为标准治疗的辅助治疗。此外，这项技术还可以应用于其他癌症和传染病，这些项目正处于临床前开发阶段。