Immunotherapy for Renal Cell Carcinoma

肾细胞癌的免疫治疗

• 批准号: 6931588
• 负责人: MARC S ERNSTOFF
• 金额: $ 35.16万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-04 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931588
• 关键词: clinical research; clinical trial phase II; combination cancer therapy; dendritic cells; human subject; human therapy evaluation; interferon alpha; interleukin 2; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; renal cell carcinoma

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.

描述（由申请人提供）：RCC的医学治疗主要集中在旨在调动识别和摧毁癌症的免疫效应细胞的生物疗法上。白细胞介素-2 （IL-2）和干扰素- α (ifn - α)治疗，无论是单独治疗还是联合治疗，在少数转移性肾癌患者中显示出显著的临床疗效。大多数患者没有获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）是细胞和肱骨免疫反应的强大启动器，在癌症模型中具有治疗效益。初步的人体研究表明，DC疗法对RCC患者具有临床和生物学有效性。然而，有证据表明免疫抑制途径可能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利用免疫活性的互补途径。DC疫苗、IL-2和ifn - α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。ifn - α通过诱导MHC分子和肿瘤相关抗原的表达，增强DC细胞和t细胞的功能以及肿瘤免疫原性。我们假设联合序贯DC疫苗和IL-2/ ifn - α治疗将降低RCC患者的肿瘤特异性免疫抑制并增加肿瘤特异性免疫激活。我们建议在33例RCC患者的H期临床试验中验证这一假设。作为标准治疗切除的原发肿瘤将进行自体疫苗的处理。符合条件和同意的转移性肾细胞癌患者将接受白细胞分离术以获得外周血单核细胞来源的dc。载有自体肿瘤裂解液的树突状细胞经超声引导注入腹股沟淋巴结，并联合IL-2和ifn - α治疗。我们建议确定1)治疗的客观临床反应率，2)联合治疗的毒性谱，3)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。