IMMUNOTHERAPY WITH RENAL TUMOR RNA TRANSFECTED CELLS

这一建议的总体假设是，肿瘤抗原特异性T细胞的激活将防止肿瘤的复发和转移。转移性肾细胞癌(RCC)患者外周血中针对RCC相关抗原的细胞毒性T细胞的频率很低或检测不到。在这项建议中，我们假设递增剂量的肿瘤RNA转染树突状细胞给转移性肾癌患者将导致可检测到的循环中功能活跃的肿瘤特异性T细胞水平。我们开发了一种新的、广泛适用的、临床上可行的免疫策略，利用转染了编码肿瘤抗原的RNA的树突状细胞(DC)在肾癌患者中诱导出显著水平的肿瘤抗原特异性T细胞。该计划计划扩展这组研究人员的基础研究和临床观察，以探索肿瘤RNA转染树突状细胞的免疫治疗的临床应用，并解决总体假设，特别是在癌症患者中产生和表征肿瘤抗原特异性T细胞。一项正在进行的主动免疫治疗的I期临床试验证明，在晚期前列腺癌患者中，用编码广泛表达的肿瘤抗原-前列腺特异性抗原(PSA)的RNA转基因的DC是安全和可行的。对免疫后患者的初步分析表明，PSA特异性T细胞被诱导，表明该疫苗策略的生物活性。为了扩大这一策略的潜力并避免针对任何单一确定的肿瘤抗原的潜在陷阱，我们建议使用TALL：肿瘤来源的RNA转基因DC来免疫患者，我们已经证明这种方法可以诱导针对广泛的肿瘤抗原的免疫反应，而不需要事先确定或了解每个患者的抗原谱。拟议的计划将为最终试验奠定基础，这些试验旨在证明在癌症患者中使用RNA转基因DC疫苗诱导肿瘤抗原特异性T细胞以减少癌症复发和转移的临床益处。

The overall hypothesis of this proposal is that the activation of tumor antigen specific T cells will prevent tumor recurrence and metastasis. The frequency of cytotoxic T cells circulating in the peripheral blood of patients with metastatic renal cell carcinoma (RCC) and directed against RCC associated antigens is low or undetectable. In this proposal, we hypothesize that administration of escalating doses of tumor RNA transfected DC to patients with metastatic RCC will lead to detectable levels of circulating, functionally active tumor specific T cells. We have developed a novel, broadly applicable, and clinically feasible immunization strategy, using dendritic cells (DC) transfected with RNA encoding tumor antigens to elicit significant levels of tumor antigen specific T cells in patients with RCC. This program proposes to extend the basic research and clinical observations from this group of investigators to explore the clinical use of immunotherapy with tumor RNA transfected DC and address the overall hypothesis, specifically to generate and characterize tumor antigen specific T cells in patients with cancer. An ongoing phase I clinical trial of active immunotherapy with DC transfected with RNA encoding a widely expressed tumor antigen, prostate specific antigen (PSA), has demonstrated the safety and feasibility of this approach in patients with advanced prostate carcinoma. Preliminary analysis of patients following immunization demonstrates the induction of PSA specific T cells, suggesting the bioactivity of this vaccine strategy. To broaden the potential of this strategy and to avoid the potential pitfalls of targeting any single defined tumor antigen, we propose immunizing patients using total: tumor derived RNA transfected DC which we have demonstrated to elicit immune responses against a broad repertoire of tumor antigens and will not require prior determination or knowledge of the antigenic profile of each patient. The proposed program will set the stage for definitive trials designed to demonstrate a clinical benefit of inducing tumor antigen specific T cells in cancer patients using RNA transfected DC vaccines to reduce cancer recurrence and metastasis.