Biologic therapy of Melanoma and Renal Cell Cancer

描述(由申请人提供)：这项K24职业中期研究人员奖的申请概述了以患者为导向的研究计划，涉及使用免疫治疗策略治疗黑色素瘤和肾细胞癌(RCCA)。首席研究员迈克尔·B·阿特金斯医学博士在1987年参加了肿瘤学培训。他在生物治疗领域是一位卓有成效的临床研究人员，作为从事癌症相关临床研究工作的研究员和初级教员的导师，他有着良好的业绩记录。他在职业生涯的大部分时间里致力于黑色素瘤和RCCA基于细胞因子的疗法的研究，并为FDA批准这两种疾病的高度封闭IL-2疗法做出了主要贡献。他最近的努力集中于通过与其他细胞因子或化疗相结合、使用选择性毒性阻滞剂、使用其他具有更有前景的治疗方案的细胞因子，或者针对最有可能有反应的患者进行治疗，来提高细胞因子治疗的治疗指数。本申请的第一部分，包括5个具体目标和7个临床试验，涉及这项工作的最新扩展。AIM 1将使用从黑色素瘤患者身上获得的系列血液、肿瘤和淋巴结样本，这些样本来自参加III或IV期疾病的两个第三阶段组间试验(由阿特金斯博士领导)的黑色素瘤患者，以确定对基于细胞因子的治疗的敏感性和耐药性的潜在机制。目的2将在两个针对RCCA患者的CWG试验的背景下，研究T细胞受体和DC功能障碍在介导IL-2治疗抵抗中所起的作用。AIM3将使用我们之前单独使用IL-12进行的翻译研究得出的策略，检查将IL-2添加到IL-12治疗中的价值。AIM4将测试一种新的IL-2选择性结合高亲和力IL-2受体的能力，将免疫激活与毒性分离。最后，Aim5将检查之前CWG IL-2试验中RCCA患者的病理材料，当IS对即将接受IL-2治疗的患者预期获得的肿瘤组织进行基因表达分析时，以确定病理和分子相关性或反应和耐药性。这项申请的第二部分，包括2个AIMS和3个额外的临床试验，将探索旨在克服肿瘤特异性耐受的新的免疫治疗策略。正在积极研究的两种方法是DC疫苗：肿瘤融合细胞(AIM 6)和非清髓性异基因干细胞移植(AIM 7)。最终目标是将这些策略中的一种或两种与基于细胞因子的治疗相结合(结合在具体目标1-5中吸取的经验教训)，以产生针对这两种疾病的更有效的免疫治疗方法。这些项目为研究员或初级教员在临床研究和实验室导师的指导下进行以患者为导向的临床研究提供了至少四条明确定义的途径。与阿特金斯博士的定期会议、多学科会议、重点临床轮换和临床调查课程将使实习生经历更加充实。总而言之，这项工作应该确定对黑色素瘤或RCCA患者成功进行免疫治疗的关键因素，同时为下一批临床研究人员提供极好的培训，他们将被指望扩大这一努力。

DESCRIPTION (provided by applicant): This K24 Midcareer Investigator Award application outlines of program of patient-oriented research involving the use of immunotherapy strategies for the treatment of melanoma and renal cell carcinoma (RCCA). The principal investigator, Michael B. Atkins, M.D., competed his oncology training in 1987. He is an accomplished clinical investigator in the areas of biologic therapy and has a proven track record as a mentor for fellows and junior faculty pursuing careers in cancer related clinical investigation. He has devoted much of his career to the investigation of cytokine he-based therapies for melanoma and RCCA and was a major contributor to the FDA approval of high-close IL-2 therapy for these two diseases. His more recent efforts have focused on enhancing the therapeutic index of cytokine therapy either through combinations with other cytokines or chemotherapy, administration of selective toxicity blocking agents, the use of other cytokines with more promising therapeutic profiles, or the targeting of treatment to those most likely to respond. The first part of this application, encompassing 5 Specific Aims and 7 clinical trials, deals with the latest extensions of this work. Aim 1 will use serial blood, tumor and lymph node specimens obtained from melanoma patients participating in the two Phase III Intergroup trials for Stage III or IV disease (led by Dr. Atkins) to determine the mechanisms underlying sensitivity and resistance to cytokine-based therapy. Aim 2 will examine the roles that T cell receptor and DC dysfunction play in mediating resistance to IL-2 therapy in the context of two CWG trials for patients with RCCA. Aim3 will examine the value of adding IL-2 to IL-12 therapy using strategies derived from our prior translational research studies with IL-12 alone. Aim4 will test the ability of a novel IL-2 that selectively binds the high affinity IL-2 receptor, to dissociate immune activation from toxicity. Finally, Aim5 will examine pathology material from RCCA patients on prior CWG IL-2 trials, as when is perform gene expression analysis on prospectively obtained tumor tissue from patients about to receive IL-2, in order to determine pathologic and molecular correlates or response and resistance. A second component of this application, involving 2 Aims and 3 additional clinical trials, will explore novel immunotherapy strategies aimed at overcoming tumor-specific tolerance. Two approaches that are actively being studied are vaccination with DC: tumor fusion cells (Aim 6) and non-myeloablative allogeneic stem cell transplantation (Aim 7). The ultimate goal is to combine one or both of these strategies with cytokine based treatment (incorporating the lessons learned in specific aims 1-5) to produce more effective immunotherapy approaches for these two diseases. These projects provide at least four clearly defined paths for fellows or junior faculty members to pursue patient-oriented clinical research under the guidance of clinical research and laboratory mentors. Regular meetings with Dr. Atkins, multidisciplinary conferences, focused clinical rotations, and a clinical investigation course will round out the trainee experience. Taken together, this work should determine the factors critical to the successful immunotherapy of patients with melanoma or RCCA and, at the same time, provide superb training for the next cadre of clinical investigators who will be counted on to extend this effort.