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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 直到最近，肾细胞癌（RCC）的医学治疗一直专注于旨在动员识别和破坏癌症的免疫效应细胞的生物疗法（1）。 一种生物疗法，白细胞介素-2（IL-2），诱导持久的完全缓解（治愈），但仅在少数（6%）转移性（m）RCC患者中（2）。 我们最近在18例接受自体肿瘤裂解物树突状细胞（DC）疫苗、IL-2和干扰素（IFN-α）治疗的mRCC患者中观察到50%的客观缓解率[16%的完全缓解（CR）]（10）。 针对破坏血管内皮生长因子（VEGF）通路以及其他肿瘤增殖和血管信号通路的新药物已证明在mRCC患者的治疗中具有显著获益（3、4、5）。 这些新疗法可以稳定疾病或导致部分缓解，但很少诱导CR或治愈。 RCC患者中循环VEGF升高与对IL-2的不良反应相关，可能是该人群中肿瘤特异性免疫失调的原因（6，7）。 已证明阻断VEGF通路可阻碍调节性/抑制性T细胞并重建免疫能力（8）。 基于我们DC疫苗临床试验中的观察结果和对VEGF途径的新理解，我们建议测试VEGF阻断联合免疫治疗是否可以增强mRCC患者的临床结局（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).