Dendritic Cell-Mediated Prostate Cancer Immunotherapy

描述(申请人提供)：在美国和欧洲男性中，前列腺癌是最常见的癌症形式，是仅次于肺癌的癌症相关死亡的主要原因。仅在2001年，美国就有19.8万例新诊断和3.15万例死亡。虽然自常规PSA筛查出现以来，检测和诊断已经显著改善，但自1940年代S引入雄激素治疗以来，治疗方案和死亡率没有重大改善。这项第一阶段的建议旨在启动有效和成本效益高的DNA疫苗的开发，方法是使用一项专利技术，允许肿瘤相关抗原(TAA)直接呈递给树突状细胞，激活CD8+细胞毒性T淋巴细胞(CTL)反应，抗体反应，以及最重要的，强大的CD 4+辅助T细胞(Th)反应。CD4+辅助T细胞有助于免疫应答的形成，并在免疫记忆的形成中发挥关键作用；因此，CD4+应答的激发应该会导致一种疫苗产品，当与基于DNA的递送平台一起使用时，该疫苗产品既有效又经济。PSMA(前列腺特异性膜抗原)是一种TAA，其表达模式几乎仅限于前列腺，已知在转移性疾病中上调。第一阶段SBIR研究将通过将PSMA TAA整合到专有疫苗构建中并在免疫的C57BL/6小鼠中表征抗体、CD4+特异性Th和CD8+特异性CTL反应来证明原则证据。此外，还将进行肿瘤挑战研究，以证明这种免疫反应在体内的生物学相关性。

DESCRIPTION (provided by applicant): In American and European men, prostate cancer is the most commonly diagnosed form of cancer and is second only to lung cancer as the leading cause of cancer-related death. In 2001 alone, there were 198,000 new diagnoses and 31,500 deaths in the United States. While detection and diagnosis have markedly improved since the advent of routine PSA screening, there have been no major improvements in treatment regimens nor changes in mortality since the introduction of androgen therapy in the 1940's. This Phase I proposal seeks to initiate the development of an efficacious and cost-effective DNA vaccine by using a proprietary technology that allows tumor-associated antigens (TAAs) to be presented directly to dendritic cells, activating CD8+ cytotoxic T-lymphocyte (CTL) responses, antibody responses, and, most-importantly, a robust CD4+ helper T-cell (Th) response. CD4+ helper T-cells aid in the brchestration of the immune response and play a key role in the formulation of immunological memory; thus, the elicitation of a CD4+ response should result in a vaccine product which is both efficacious and cost-effective when used in conjunction with a DNA-based delivery platform. PSMA (prostate-specific membrane antigen) is a TAA with an expression pattern limited almost exclusively to the prostate and is known to be up-regulated in metastatic disease. Phase I SBIR research will demonstrate proof of principle by incorporating the PSMA TAA into the proprietary vaccine construct and characterizing antibody, CD4+-specific Th, and CD8+-specific CTL responses in immunized C57BL/6 mice. Additionally, a tumor challenge study will be performed to demonstrate the biological relevance of this immune response in vivo.