Alphavirus prime-boost vaccines for prostate cancer

描述（由申请人提供）： 前列腺癌是美国男性癌症死亡的第二大原因， 迫切需要新的治疗方法。虽然雄激素消融 暂时控制转移性疾病，几乎所有的肿瘤最终都会成为 难治性，然后迅速进展，因为没有其他有效的 治疗 前列腺特异性膜抗原（PSMA）是一种剪接变体， 跨膜结构域，从而保留在细胞质中的正常 前列腺上皮细胞相比之下，在前列腺癌细胞上， 作为具有大的胞外结构域的膜糖蛋白。的这种模式 表达使得PSMA成为主动免疫疗法的引人注目的靶标。 我们的总体目标是开发和临床评估PSMA疫苗。我们 正在研究传统的纯化蛋白疫苗和新型病毒载体 最终单独使用和以异源初免-加强组合使用的疫苗 甲病毒复制子和佐剂化蛋白疫苗是理想的 补充与潜在的介导广泛的有效，保护性 体内细胞和体液免疫应答。 在这个I期项目中，我们将进行关键的临床前开发， 生产和表征新甲病毒复制子的活动， 塞姆利基森林病毒，表达不同形式的PSMA。人HLA-A2 将采用转基因动物模型来测量质量和 通过以下的初免-加强组合在体内引发的免疫应答的幅度 PSMA疫苗，这些数据将推动新型免疫疗法的选择 用于临床试验

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in American males, and there is an urgent need for novel therapeutics. Although androgen ablation temporarily controls metastatic disease, almost all tumors eventually become hormone-refractory and then rapidly progress since there is no other effective treatment. Prostate-specific membrane antigen (PSMA) is a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm in normal prostate epithelial cells. In contrast, on prostate cancer cells, PSMA exists as a membrane glycoprotein with a large extracellular domain. This pattern of expression makes PSMA a compelling target for active immunotherapy. Our overall goal is to develop and clinically evaluate PSMA-based vaccines. We are pursuing both traditional purified protein vaccines and novel viral vector vaccines for eventual use alone and in heterologous prime-boost combinations in man. Alphavirus replicons and adjuvanted protein vaccines are ideal complements with the potential to mediate a wide array of potent, protective cellular and humoral immune responses in vivo. In this Phase I project, we will perform critical preclinical development activities to produce and characterize new alphavirus replicons, based on Semliki Forest virus, that express distinct forms of PSMA. A human HLA-A2 transgenic animal model will be employed to measure the quality and the magnitude of immune responses elicited in vivo by prime-boost combinations of PSMA vaccines, and these data will drive the selction of novel immunotherapies for clinical trials.