Alphavirus prime-boost vaccines for prostate cancer

前列腺癌甲病毒初免加强疫苗

• 批准号: 6665112
• 负责人: Jason Gardner
• 金额: $ 18.13万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665112
• 关键词: Semliki Forest virus; active immunization; bioreactors; cell mediated lymphocytolysis test; cellular immunity; enzyme linked immunosorbent assay; genetically modified animals; humoral immunity; laboratory mouse; male; method development; neoplasm /cancer vaccine; prostate neoplasms; prostate specific antigen; protein folding; protein purification; recombinant proteins; recombinant virus; surface antigens; vaccine development; vector vaccine

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.

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。尽管雄激素消融 暂时控制转移性疾病，几乎所有肿瘤最终都会变成 激素难治性，然后由于没有其他有效的治疗方法而迅速进展 治疗。 前列腺特异性膜抗原 (PSMA) 是一种剪接变体，缺乏 跨膜结构域，从而在正常情况下保留在细胞质中 前列腺上皮细胞。相反，在前列腺癌细胞上，PSMA 存在 作为具有大胞外结构域的膜糖蛋白。这种模式的 表达使 PSMA 成为主动免疫疗法的引人注目的靶点。 我们的总体目标是开发和临床评估基于 PSMA 的疫苗。我们 正在寻求传统的纯化蛋白疫苗和新型病毒载体 最终单独使用和异源初免-加强组合的疫苗 在人身上。甲病毒复制子和佐剂蛋白疫苗是理想的选择 具有介导多种有效、保护性作用的潜力 体内细胞和体液免疫反应。 在这个第一阶段项目中，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，基于 Semliki 森林病毒，表达不同形式的 PSMA。人类 HLA-A2 将采用转基因动物模型来测量质量和 通过初免-加强组合在体内引发的免疫反应的强度 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。