Lymphodepletion for Melanoma Patients

描述(申请人提供)：转移性黑色素瘤(MM)的医学治疗主要集中在生物疗法上，旨在动员识别和摧毁癌症的免疫效应细胞。白介素2(IL-2)治疗少数多发性骨髓瘤患者显示出显著的临床疗效。大多数患者没有受益可能是由于肿瘤耐药和/或效应细胞反应不足。淋巴因子激活的杀伤细胞(LAK)或肿瘤浸润性淋巴细胞(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的问题。不幸的是，针对多发性骨髓瘤患者的随机试验未能证实在大剂量IL-2的基础上加用细胞疗法的益处。过继细胞治疗的失败可能与持续的耐受因素或淋巴体内细胞毒效应细胞增殖空间不足有关。化疗导致淋巴枯竭，随后大剂量IL-2过继转移选定的体外扩大的TIL，在大约50%的MM患者中诱导了显着的反应。实验室研究表明，淋巴枯竭本身就能创造出一种抗肿瘤的免疫环境，能够诱导肿瘤的消退。在淋巴耗竭后，T细胞发生动态平衡的重新繁殖，抗原特异的T记忆细胞和初始T细胞被抗原提呈细胞偏向抗原特异的效应细胞。粒细胞巨噬细胞集落刺激因子(GM-CSF)可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)的淋巴净化将为GM-CSF和IL-2驱动的黑色素瘤导向的溶细胞淋巴细胞群的从头再生抗原提呈细胞提供一个肥沃的环境，随后临床受益。我们建议在一个两阶段的第二阶段研究中检验这一假设。符合条件的和同意的MM患者将接受大剂量C(第1，2天)和F(第3-7天)的治疗，然后接受2个5天的大剂量IL-2疗程，间隔9天休息。GM-CSF将从第8天开始注射。有反应的患者将接受第二个疗程的IL-2治疗。我们建议确定1)治疗的完全应答率和部分应答率，2)使用该方案的毒性，3)淋巴细胞和树突状细胞恢复的动力学、表型和功能，4)进展和存活的时间，5)淋巴细胞恢复与客观临床反应的关系。

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.