Listeria-Based Vaccines for Ovarian Cancer Therapy

说明(申请人提供)：卵巢癌是妇科恶性肿瘤患者中死亡率最高的疾病，每年约有14,000人死于癌症。患有晚期疾病的女性两年复发率超过50%，五年存活率不到50%。该提案的目的是确定编码肿瘤抗原间硫蛋白的基于单核细胞增多性李斯特菌的癌症疫苗的最佳配置，用于卵巢癌的靶向免疫治疗。李斯特菌是一种细胞内细菌，能够激发强大的CD4+/CD8+T细胞介导的反应，在感染疾病和癌症的动物模型中具有显著的效力，并已在健康的人类志愿者身上进行了测试。间皮蛋白是一种分化抗原，在95%的卵巢癌中表达，在其他癌症中表达水平较低，但除间皮细胞外，在包括正常卵巢在内的各种正常组织中均未检测到。一组表达间皮蛋白的重组李斯特菌将被衍生出来，并在新开发的表达间皮蛋白并重现人类卵巢癌的同基因小鼠模型中测试治疗效果。实现这些目标将为第二阶段SBIR奠定基础，将该项目推向晚期卵巢癌女性的临床试验。

DESCRIPTION (provided by the applicant): Ovarian cancer causes the highest mortality rate among women with gynecologic malignancy, approximately 14,000 cancer deaths per year. Women with late-stage disease have a 2-year relapse rate of more than 50%, and a 5-year survival rate of less than 50%. The goal of this proposal is to identify the optimal configuration of a Listeria monocytogenes-based cancer vaccine encoding the tumor antigen mesothelin, for application as a targeted immunotherapy for ovarian cancer. Listeria is an intracellular bacterium that primes robust CD4+/CD8+ T-cell mediated responses, has striking potency in animal models of both infectious disease and cancer, and has been tested in healthy human volunteers. Mesothelin is a differentiation antigen that is expressed in 95% of ovarian cancers and lower levels in other cancers, but other than mesothelial cells, is not detected in diverse normal tissues, including normal ovaries. A panel of recombinant Listeria that express mesothelin fused to elements that augment antigen presentation will be derived, and tested for therapeutic efficacy in a newly-developed syngeneic mouse model that expresses mesothelin and recapitulates human ovarian cancer. Accomplishing these goals will set the stage in a Phase II SBIR for moving the project toward a clinical trial in women with advanced ovarian cancer.