IMMUNOTHERAPY WITH RENAL TUMOR RNA TRANSFECTED CELLS

该建议的总体假设是肿瘤抗原特异性T细胞的激活将阻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细胞循环频率低或检测不到。在这一建议中，我们假设给转移性RCC患者递增剂量的肿瘤RNA转染DC将导致可检测到的循环、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、临床可行的免疫策略，使用树突状细胞（DC）转染编码肿瘤抗原的RNA，在RCC患者中引起显著水平的肿瘤抗原特异性T细胞。本项目拟扩展本课组的基础研究和临床观察，探索肿瘤RNA转染DC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I期临床试验表明，DC转染RNA编码广泛表达的肿瘤抗原，前列腺特异性抗原（PSA）的主动免疫治疗已经证明了这种方法在晚期前列腺癌患者中的安全性和可行性。对免疫后患者的初步分析表明，该疫苗可诱导PSA特异性T细胞，表明该疫苗策略具有生物活性。为了扩大这一策略的潜力，并避免针对任何单一肿瘤抗原的潜在陷阱，我们建议使用肿瘤衍生的RNA转染DC对患者进行免疫，我们已经证明该方法可以引发针对广泛肿瘤抗原的免疫反应，并且不需要事先确定或了解每个患者的抗原谱。拟议的项目将为最终试验奠定基础，旨在证明使用RNA转染的DC疫苗在癌症患者中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.