Lymphodepletion for Melanoma Patients

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动员识别和破坏癌症的免疫效应细胞的生物疗法。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。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。使用淋巴因子激活的杀伤细胞（LAK）或肿瘤浸润淋巴细胞（TIL）和IL-2的过继性细胞疗法已被用来克服效应细胞反应不足的问题。不幸的是，MM患者的随机试验未能证实在高剂量IL-2的基础上加入细胞疗法的益处。过继性细胞治疗的失败可能与持续的致耐受性因子或淋巴区室中细胞毒性效应细胞增殖的空间不足有关。化疗诱导的淋巴细胞清除，随后高剂量IL-2与选定的离体扩增的TIL的过继转移在约50%的MM患者中诱导了显著的应答。实验室研究已经证明，淋巴细胞清除单独创建能够诱导肿瘤消退的抗肿瘤免疫环境。淋巴细胞耗竭后，T细胞的稳态再增殖发生在抗原特异性T记忆细胞和通过抗原呈递细胞偏向抗原特异性效应细胞的初始T细胞中。粒细胞-巨噬细胞集落刺激因子（GM-CSF）增强抗原呈递细胞的数量和功能。因此，我们假设用环磷酰胺（C）和氟达拉滨（F）进行淋巴细胞清除将为GM-CSF和IL-2驱动的黑素瘤定向溶细胞淋巴细胞群的抗原呈递细胞从头再生提供肥沃的环境，随后具有临床益处。我们建议在2阶段II期研究中检验这一假设。合格且同意的MM患者将接受高剂量C（第1、2天）和F（第3-7天）治疗，随后接受2个为期5天的高剂量IL-2疗程，间隔9天休息。将从第8天开始给予GM-CSF。在有反应的患者中，将给予第二个疗程的IL-2。我们建议确定1）对治疗的完全和部分应答率，2）给予该方案的毒性特征，3）淋巴细胞和树突状细胞恢复的动力学、表型和功能，4）进展和存活时间，以及5）淋巴细胞恢复与客观临床应答的关系。

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.