Immunotherapy for Renal Cell Carcinoma

描述（由申请人提供）：RCC的医学治疗主要集中在旨在动员识别和破坏癌症的免疫效应细胞的生物疗法。用白细胞介素-2（IL-2）和干扰素α（IFN α）单独或联合治疗在少数转移性RCC患者中显示出显著的临床疗效。在大多数患者中缺乏益处可能是由于肿瘤抗性和/或效应细胞应答不足。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有力的启动剂，并在癌症模型中具有治疗益处。初步的人体研究表明，DC疗法在RCC患者中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利用免疫活性的互补途径。DC疫苗、IL-2和IFN α影响免疫激活和抑制的不同途径。DC疫苗可以启动，有时维持有效的抗肿瘤免疫应答。IL-2诱导T细胞活化和增殖，并且可以克服CTLA-4对活化的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和T细胞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治疗将减少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性肿瘤将被处理用于自体疫苗。符合条件并同意的转移性RCC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。通过超声引导注射到腹股沟淋巴结中施用的负载有自体肿瘤裂解物的DC将与IL-2和IFN α治疗组合。我们建议确定1）对治疗的客观临床应答率，2）该联合治疗的毒性特征，3）治疗相关的肿瘤特异性免疫应答和4）肿瘤特异性免疫应答与客观临床应答的关系。

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.