Immunotherapy for Renal Cell Carcinoma

描述（由申请人提供）：转移性肾细胞癌（mRCC）的生物疗法，如阿地白介素（IL-2），旨在动员识别和破坏癌症的免疫效应细胞。IL-2诱导持久的完全缓解（CR），但仅在少数患者中。我们最近在用自体肿瘤裂解物-树突状细胞（DC）-疫苗、IL-2和干扰素（IFNa）治疗的mRCC患者中观察到50%的客观缓解率（16% CR）。抑制血管内皮生长因子（VEGF）通路的新药物在mRCC患者中也显示出显著获益，但很少诱导CR。高血液VEGF与对IL-2的不良反应相关，并可导致肿瘤特异性免疫失调。阻断VEGF途径已被证明可以阻碍调节性/抑制性T细胞并重建免疫能力。为了测试免疫激活和调节途径破坏的互补机制是否增强结果，我们计划在重新设计的II期试验中使用贝伐单抗、DC疫苗、IL-2和IFNa治疗24例mRCC患者。该项目的观察结果将用于开发新的癌症疗法，如果成功，将减少癌症对公众的负担。DC启动细胞和体液免疫应答，但在VEGF存在下功能障碍。IL- 2诱导T细胞活化和增殖并逆转获得性T细胞缺陷。IFNa通过表达MHC分子和肿瘤相关抗原增强肿瘤免疫原性，并且可以增强DC和T细胞功能。VEGF阻断可以抑制调节细胞并恢复DC的功能。贝伐珠单抗是FDA批准的在mRCC中具有活性的抗VEGF抗体，与IL-2或IFNa一起施用是安全的。作为标准护理移除的RCC将被处理用于自体疫苗。符合条件且知情同意的mRCC患者将接受白细胞去除术，以获得外周血单核细胞衍生的DC。贝伐珠单抗将在超声引导的淋巴结注射负载有自体肿瘤裂解物的DC之前施用，然后进行IL-2 + IFNa治疗。我们建议确定1）对治疗的客观临床应答率和无进展生存期，2）治疗的临床和自身免疫相关毒性特征，以及3）治疗相关的肿瘤特异性免疫应答以及肿瘤特异性免疫应答与客观临床应答的关系。公共卫生相关性：我们的新型治疗方法将提供原理证明，即使用联合治疗（贝伐单抗，DC + IL-2/IFNa）调节炎症和抑制性免疫途径可以克服免疫抵抗并增强临床活性。该项目的观察结果将用于开发新的和原始的癌症疗法，如果成功，将减少癌症对公众的负担。

DESCRIPTION (provided by applicant): Biological therapies, such as aldesleukin (IL-2), for metastatic renal cell carcinoma (mRCC) are designed to mobilize immune effector cells that recognize and destroy cancer. IL-2 induces durable complete remissions (CR) but only in a minority of patients. We have recently observed a 50% objective response rate (16% CR) in mRCC patients treated with autologous tumor lysate-dendritic cell (DC)-vaccine, IL-2 and interferon (IFNa). New agents inhibiting vascular endothelial growth factor (VEGF) pathways have demonstrated significant benefit in mRCC patients as well, but rarely induce CRs. High blood VEGF is associated with poor response to IL-2 and can cause tumor specific immune dysregulation. Blocking VEGF pathways has been demonstrated to impede regulatory/inhibitory T cells and re-establish immune competency. To test whether complementary mechanisms of immune activation and disruption of regulatory pathways enhance outcome we plan to treat 24 mRCC patients in a redesigned phase II trial using bevacizumab, DC vaccine, IL-2, and IFNa. Observations from this project will be used in the development of novel cancer therapies which, if successful, will decrease the burden of cancer on the public. DCs initiate cellular and humoral immune responses but are dysfunctional in the presence of VEGF. IL- 2 induces T-cell activation and proliferation and reverses acquired T-cell defects. IFNa enhances tumor immunogenicity through expression of MHC molecules and tumor associated antigens, and can enhance DC and T-cell function. VEGF blockade can inhibit regulatory cells and restore function to DCs. Bevacizumab, an FDA approved anti-VEGF antibody with activity in mRCC, is safe to administer with IL-2 or IFNa. RCC removed as standard care will be processed for autologous vaccine. Eligible and consented patients with mRCC will undergo leukaphereses to obtain peripheral blood monocyte derived DCs. Bevacizumab will be administered prior to ultrasound guided lymph node injections of DCs loaded with autologous tumor lysate and followed by IL-2 + IFNa therapy. We propose to determine 1) the objective clinical response rate to treatment and progression free survival, 2) the clinical and autoimmune related toxicity profile of therapy, and 3) the treatment related tumor-specific immune response and the relationship of tumor-specific immune response and objective clinical response. PUBLIC HEALTH RELEVANCE: Our novel therapeutic approach will provide proof of principle that regulation of both inflammatory and inhibitory immune pathways using combination therapy (bevacizumab, DCs + IL-2/IFNa) can overcome immune resistance and enhance clinical activity. Observations from this project will be used in the development of new and original cancer therapies which, if successful, will decrease the burden of cancer on the public.