Immunotherapy for Renal Cell Carcinoma

描述(申请人提供)：转移性肾细胞癌(MRCC)的生物疗法，如白介素2(IL-2)，旨在动员免疫效应细胞识别和摧毁癌症。IL-2可诱导持久的完全缓解(CR)，但仅在少数患者中有效。我们最近观察到，在接受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，有50%的客观有效率(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的益处，但很少导致CRS。血中高水平的血管内皮生长因子与IL-2反应不良有关，并可导致肿瘤特异性免疫失调。阻断血管内皮生长因子途径已被证明阻碍调节/抑制T细胞和重建免疫能力。为了测试免疫激活和调节通路中断的互补机制是否会改善预后，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名mRCC患者。这个项目的观察结果将被用于开发新的癌症疗法，如果成功，将减轻公众的癌症负担。DC启动细胞和体液免疫反应，但在血管内皮生长因子存在的情况下功能障碍。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，并能增强DC和T细胞功能。阻断血管内皮生长因子可以抑制调节性细胞，恢复DC的功能。贝伐单抗是FDA批准的一种抗血管内皮生长因子抗体，在mRCC中具有活性，与IL-2或IFNA一起使用是安全的。作为标准护理被移除的RCC将被处理为自体疫苗。符合条件的和同意的肾细胞癌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向装有自体肿瘤裂解物的树突状细胞注射之前给予，随后进行IL-2+IFNA治疗。我们建议确定1)治疗和无进展生存率的客观临床应答率，2)治疗的临床和自身免疫相关毒性，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则证据，证明使用联合疗法(贝伐单抗、DC+IL-2/IFNA)调节炎症和抑制性免疫通路可以克服免疫耐药，提高临床活性。这个项目的观察结果将被用于开发新的和原始的癌症治疗方法，如果成功，将减轻公众的癌症负担。

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.