Immunotherapy for Renal Cell Carcinoma

描述(申请人提供)：肾癌的医学治疗主要集中于生物疗法，旨在动员识别和摧毁癌症的免疫效应细胞。白介素2(IL-2)和干扰素α(IFNpha)单独或联合治疗对少数转移性肾癌患者显示出显著的临床疗效。大多数患者没有受益可能是由于肿瘤耐药和/或效应细胞反应不足。体外和动物研究表明，树突状细胞(DC)是细胞和体液免疫反应的强大启动者，在癌症模型中具有治疗作用。初步的人体研究表明DC疗法对肾癌患者具有临床和生物学效果。然而，有证据表明，免疫抑制途径可能会限制免疫治疗的有效性，包括DC疫苗。联合免疫疗法的主要目标是成功地开发免疫活动的互补途径。DC疫苗、IL-2和IFNα影响不同的免疫激活和抑制途径。DC疫苗可以启动并有时维持有效的抗肿瘤免疫反应。IL-2可诱导T细胞活化和增殖，并能克服CTLA-4对活化T细胞的负抑制作用。干扰素通过诱导MHC分子和肿瘤相关抗原的表达来增强DC和T细胞的功能以及肿瘤的免疫原性。我们假设，联合序贯DC疫苗和IL-2/IFNα治疗将减少肾癌患者的肿瘤特异性免疫抑制，增加肿瘤特异性免疫激活。我们建议在33名肾癌患者的H期临床试验中验证这一假设。作为标准护理切除的原发肿瘤将被处理为自体疫苗。符合条件的和同意的转移性肾癌患者将接受白细胞分离以获得外周血单核细胞来源的DC。超声引导下腹股沟淋巴结内注射自体肿瘤裂解物的DC将与IL-2和IFNα联合治疗。我们建议确定1)治疗的客观临床应答率，2)联合治疗的毒副作用，3)与治疗相关的肿瘤特异性免疫反应，4)肿瘤特异性免疫反应与客观临床反应的关系。

DESCRIPTION (provided by applicant): Medical treatment for RCC has primarily focused on biological therapies designed to mobilize immune effector cells that recognize and destroy cancer. Treatment with interleukin-2 (IL-2) and interferon alpha (IFNalpha), either singly or in combination, have shown dramatic clinical efficacy in a minority of metastatic RCC patients. The absence of benefit in the majority of patients may be due to tumor resistance and/or inadequate effector cell response. In vitro and animal studies show that dendritic cells (DC) are powerful initiators of cellular and humeral immune response and have therapeutic benefit in cancer models. Preliminary human studies suggest DC therapies have clinical and biological effectiveness in RCC patients. However, evidence suggests that immune inhibitory pathways may limit effectiveness of immunotherapy, including DC vaccines. The primary goal of combination immunotherapies is to successfully exploit complementary pathways of immune activity. DC vaccine, IL-2, and IFNalpha influence different pathways of immune activation and inhibition. DC vaccines can initiate, and at times sustain, an effective anti-tumor immune response. IL-2 induces T-cell activation and proliferation, and can overcome the negative inhibitory action of CTLA-4 on activated T-cells. IFNalpha enhances DC and T-cells function as well as tumor immunogenicity by inducing expression of MHC molecules and tumor associated antigens. We hypothesize that combined sequential DC vaccine and IL-2/IFNalpha therapy will decrease tumor-specific immune inhibition and increase tumor-specific immune activation in RCC patients. We propose to test this hypothesis in a phase H clinical trial of 33 RCC patients. Primary tumor removed as standard care will be processed for autologous vaccine. Eligible and consented patients with metastatic RCC will undergo leukapheresis to obtain peripheral blood monocyte derived DCs. DCs loaded with autologous tumor lysate administered by ultrasound guided injection into inguinal lymph nodes will be combined with IL-2 and IFNalpha therapy. We propose to determine 1) the objective clinical response rate to treatment, 2) the toxicity profile of this combined therapy, 3) the treatment related tumor-specific immune response and 4) the relationship of tumor-specific immune response and objective clinical response.