Lymphodepletion for Melanoma Patients

黑色素瘤患者的淋巴清除

• 批准号: 7230288
• 负责人: MARC S ERNSTOFF
• 金额: $ 27.56万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-24 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230288
• 关键词: Adoptive Transfer; Antigen-Presenting Cells; Antigens; Biological; Biological Products; Biological Response Modifier Therapy; CD8B1 gene; Cell Proliferation; Cells; Cessation of life; Clinical; Clinical Trials; Condition; Consent; Cyclophosphamide; Cytotoxic Chemotherapy; Dendritic Cells; Disease regression; Dose; Effector Cell; Environment; Failure; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Interleukin-2; Kinetics; Laboratory Study; Lymphocyte; Lymphocyte Function; Lymphoid; Lymphokine-Activated Killer Cells; Lymphokines; Malignant Neoplasms; Mediating; Medical; Memory; Metastatic Melanoma; Minority; Mus; Natural Killer Cells; Natural regeneration; Numbers; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Population; Randomized Controlled Clinical Trials; Rate; Recovery; Reporting; Resistance; Rest; Staging; Stimulus; Suppressor-Effector T-Lymphocytes; T memory cell; T-Lymphocyte; Testing; Time; Toxic effect; Treatment Protocols; Tumor-Infiltrating Lymphocytes; chemotherapy; clinical efficacy; cytotoxic; day; design; fludarabine; irradiation; melanoma; partial response; response; therapy design; tumor

DESCRIPTION (provided by applicant): Medical treatment for metastatic melanoma (MM) has primarily focused on biological therapies designed to mobilize immune, effector cells that recognize and destroy cancer. Treatment with interleukin-2 (IL-2) has shown dramatic clinical efficacy in a minority of MM patients. The absence of benefit in the majority of patients may be due to tumor resistance and/or inadequate effector cell response. Adoptive cellular therapies with lymphokine activated killer cells (LAK) or tumor infiltrating lymphocytes (TIL) and IL-2 have been employed to overcome inadequate effector cell response. Unfortunately, randomized trials in MM patients have failed to confirm benefit for the addition of cellular therapy to high dose IL-2. The failure of adoptive cellular therapy may be related to persistent tolerogenic factors or inadequate space for cytotoxic effector cell proliferation in the lymphoid compartment. Chemotherapy induced lymphodepletion followed by high dose IL-2 with adoptive transfer of selected ex vivo expanded TILs has induced significant responses in approximately 50% of MM patients. Laboratory studies have demonstrated that lymphodepletion alone creates an anti-tumor immune environment capable of inducing regression of tumors. Following lymphodepletion, homeostatic repopulation of T-cells occurs with antigen-specific T memory cells and naive T-cells skewed to antigen-specific effector cells by antigen presenting cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) enhances number and function of antigen presenting cells. Thus, we hypothesize that lymphodepletion with cyclophosphamide (C) and fludarabine (F) will provide a fertile environment for de novo regeneration of antigen presenting cells by GM-CSF and IL-2 driven melanoma-directed cytolytic lymphocyte populations with subsequent clinical benefit. We propose to test this hypothesis in a 2-stage phase II study. Eligible and consented patients with MM will undergo treatment with high dose C (day 1,2) and F (day 3-7) followed by 2 5-day courses of high-dose IL-2 separated by 9 days rest. GM-CSF will be given starting on day 8. In responding patients, a second course of IL-2 will be administered. We propose to determine 1) the complete and partial response rate to treatment, 2) the toxicity profile of administering this regimen, 3) the kinetics, phenotype and function of lymphocyte and dendritic cell recovery, 4) time to progression and survival and 5) the relationship of lymphocyte recovery and objective clinical responses.

描述（由申请人提供）：转移性黑色素瘤（MM）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）治疗在少数MM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。采用淋巴因子激活杀伤细胞（LAK）或肿瘤浸润淋巴细胞（TIL）和IL-2的过继细胞疗法已被用于克服效应细胞反应不足。不幸的是，MM患者的随机试验未能证实在高剂量IL-2的基础上增加细胞治疗的益处。过继细胞治疗的失败可能与持续的耐受性因素或淋巴细胞室中细胞毒性效应细胞增殖空间不足有关。化疗诱导淋巴细胞耗损，然后高剂量IL-2过继转移选定的体外扩展TILs，在大约50%的MM患者中诱导了显著的反应。实验室研究表明，淋巴细胞清除本身就能产生一种抗肿瘤的免疫环境，能够诱导肿瘤的消退。淋巴细胞耗损后，抗原特异性T记忆细胞和初始T细胞被抗原呈递细胞扭曲为抗原特异性效应细胞，从而发生T细胞的稳态再生。粒细胞-巨噬细胞集落刺激因子（GM-CSF）增强抗原提呈细胞的数量和功能。因此，我们假设环磷酰胺(C)和氟达拉滨(F)的淋巴消耗将为GM-CSF和IL-2驱动的黑素瘤导向的细胞溶解淋巴细胞群的抗原提呈细胞新生提供一个肥沃的环境，从而带来随后的临床益处。我们建议在一项2阶段的II期研究中验证这一假设。符合条件和同意的MM患者将接受高剂量C（第1、2天）和F（第3-7天）治疗，随后是2个5天的高剂量IL-2疗程，中间休息9天。GM-CSF将于第8天开始给予。对于有反应的患者，将给予第二个疗程的IL-2。我们建议确定1)治疗的完全缓解率和部分缓解率，2)使用该方案的毒性谱，3)淋巴细胞和树突状细胞恢复的动力学，表型和功能，4)进展和生存时间，5)淋巴细胞恢复与客观临床反应的关系。