Development of PSMA-based Vaccines for Prostate Cancer

个人描述(申请人提供)：前列腺癌居第二位 癌症是美国男性癌症死亡的主要原因，迫切需要新的疗法来治疗或预防复发和转移性疾病。 前列腺特异性膜抗原(PSMA)是一种特性良好的糖蛋白。 其表达在很大程度上局限于上皮细胞。在正常组织中， PSMA以剪接变异体的形式存在，它缺乏跨膜结构域，并且 从而保留在细胞质中。但在肿瘤细胞上，PSMA在 高水平作为一种II型膜蛋白，具有大量的细胞外 域。这种独特的表达和处理模式使PSMA成为一种高度 有吸引力的免疫治疗靶点。 我们建议开发基于PSMA的新型前列腺癌疫苗疗法。 癌症。我们已经开发出两种主要候选疫苗：一种传统的纯化疫苗 蛋白质疫苗以及新型病毒载体疫苗。此阶段I 应用程序描述了所需的关键临床前开发活动 以最佳方式将疫苗推向人体临床试验。这些活动 与疫苗的生产和它们的体外鉴定有关 在活体内。被证明能准确模拟并诱导免疫的疫苗 然后将在最好的动物模型中测试与肿瘤相关的PSMA 人前列腺癌的单独和新的优质-增强组合 第二阶段项目中的患者。 拟议的商业应用：这项提议的总体目标是开发基于PSMA的疫苗疗法，有可能在人类身上诱导强大的抗肿瘤反应。这项拟议研究确定的主要疫苗将进入临床试验，如果对人类有效，将生产用于治疗前列腺癌的商业销售。成功的免疫疗法的市场包括有复发或转移性疾病风险的男性。这将包括相当大一部分被诊断患有前列腺癌的人，即美国的179,000人。除美国以外的市场在规模上大致相同。

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in American males, and there is an urgent need for noveltherapies to treat or prevent recurrent and metastatic disease. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to epithelial cells. In normal tissues, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. But on tumor cells, PSMA is expressed at high levels as a type II membrane protein that has a large extracellular domain. This unique pattern of expression and processing makes PSMA a highly attractive target for immunotherapy. We propose the development of novel PSMA-based vaccine therapies for prostate cancer. We have developed two lead vaccine candidates: a traditional purified protein vaccine as well as a novel viral vector vaccine. This Phase I application describes the critical preclinical development activities required to optimally advance the vaccines into human clinical trials. These activities relate to production of the vaccines and their characterization both in vitro and in vivo. Vaccines that are shown to accurately mimic and induce immunity to tumor-associated PSMA in the best available animal model will then be tested individually and in novel prime-boost combinations in human prostate cancer patients in the Phase II project. PROPOSED COMMERCIAL APPLICATION: The overall goal of this proposal is to develop PSMA-based vaccine therapies with the potential to induce robust antitumor responses in man. The lead vaccines identified with this proposed research will be moved into clinical trials and, if effective in humans, will be manufactured for commercial sale for the treatment of prostate cancer. The market for a successful immunotherapy includes men who have or who are at risk for the development of recurrent or metastatic disease. This would include a significant fraction of individuals diagnosed with prostate cancer, or 179,000 individuals in the U.S. The ex-U.S. market is approximately equal in magnitude.