PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) GENE EXPRESSION IN METASTATIC RENAL CEL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 直到最近，肾细胞癌(RCC)的医学治疗一直专注于生物疗法，旨在动员识别和摧毁癌症的免疫效应细胞(1)。一种生物疗法，白介素2(IL-2)，可诱导持久的完全缓解(治愈)，但仅在转移性(M)肾癌的少数患者(6%)中有效(2)。我们最近观察了18例接受自体肿瘤裂解树突状细胞(DC)疫苗、IL-2和干扰素(干扰素-α)治疗的mRCC患者的50%客观缓解率[16%完全缓解(CR)](10)。旨在破坏血管内皮生长因子(VEGF)途径以及其他肿瘤增殖和血管信号途径的新药物在治疗mRCC患者方面显示出显著的益处(3，4，5)。这些新疗法可以稳定疾病或导致部分缓解，但很少会导致CRS或治愈。肾癌患者循环血管内皮生长因子升高与IL-2反应不良有关，并可能是该人群肿瘤特异性免疫失调的原因(6，7)。阻断血管内皮生长因子通路已被证明阻碍调节/抑制T细胞和重建免疫能力[8]。基于对DC疫苗临床试验的观察和对血管内皮生长因子途径的新认识，我们建议测试血管内皮生长因子阻断联合免疫治疗是否能改善肾细胞癌患者的临床预后(9)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Until recently, medical treatment for renal cell cancer (RCC) has focused on biological therapies designed to mobilize immune effector cells that recognize and destroy cancer (1). One biological therapy, interleukin-2 (IL-2), induces durable complete remissions (cure) but only in a minority (6%) of patients with metastatic (m) RCC (2). We have recently observed a 50% objective response rate [16% complete response (CR)] in 18 mRCC patients treated with autolotous tumor-lysate dendritic cell (DC)-vaccine, IL-2 and interferon (IFN-alpha) (10). New agents directed at disrupting the Vascular Endothelial Growth Factor (VEGF) pathways as well as other tumor proliferation and vascular signal pathways have demonstrated significant benefit in the treatment of mRCC patients (3,4,5). These new therapies can stabilize the disease or cause partial remissions, but rarely induce CRs or cures. Elevated circulating VEGF in RCC patients is associated with poor response to IL-2 and can be a cause for tumor specific immune dysregulation in this population (6,7). Blocking VEGF pathways has been demonstrated to impede regulatory/inhibitory T cells and re-establish immune competency (8). Building on observations in our DC vaccine clinical trial and new understanding of VEGF pathways we propose to test whether VEGF blockade combined with immunotherapy can enhance clinical outcome for mRCC patients (9).