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，如白介素（IL-2），旨在调动识别和破坏癌症的免疫效应细胞。IL-2可诱导持久完全缓解（CR），但仅适用于少数患者。我们最近观察到，在接受自体肿瘤裂解-树突状细胞（DC）疫苗、IL-2和干扰素（IFNa）治疗的mRCC患者中，客观有效率为50% （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的益处，但很少诱导cr。高血VEGF与IL-2反应差有关，可引起肿瘤特异性免疫失调。阻断VEGF通路已被证明可阻碍调节性/抑制性T细胞并重建免疫能力。为了测试免疫激活和调节通路破坏的互补机制是否能增强结果，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。这个项目的观察结果将用于开发新的癌症疗法，如果成功，将减轻公众的癌症负担。树突状细胞启动细胞和体液免疫反应，但在VEGF的存在下功能失调。IL- 2诱导t细胞活化和增殖，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，增强DC和t细胞功能。VEGF阻断可抑制调节细胞，恢复DCs功能。贝伐单抗是FDA批准的抗vegf抗体，在mRCC中具有活性，与IL-2或IFNa联合使用是安全的。作为标准护理去除的RCC将用于自体疫苗。符合条件和同意的mRCC患者将接受白细胞移植以获得外周血单核细胞来源的dc。贝伐单抗将在超声引导下淋巴结注射装载自体肿瘤裂解液的DCs之前施用，然后进行IL-2 + IFNa治疗。我们建议确定1)治疗的客观临床反应率和无进展生存期，2)治疗的临床和自身免疫相关毒性谱，3)治疗相关的肿瘤特异性免疫反应以及肿瘤特异性免疫反应与客观临床反应的关系。公共卫生相关性：我们的新治疗方法将提供原理证明，使用联合治疗（贝伐单抗，DCs + 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，将减轻公众对癌症的负担。

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.