Rosenberg S A, Yannelli J R, Yang J C, Topalian S L, Schwartzentruber D J, Weber J S, Parkinson D R, Seipp C A, Einhorn J H, White D E
Surgery Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Md.
J Natl Cancer Inst. 1994 Aug 3;86(15):1159-66. doi: 10.1093/jnci/86.15.1159.
Studies of human tumor-infiltrating lymphocytes (TILs) derived from patients with a variety of histologic types of cancer have demonstrated that cellular immune reactions against established malignancy exist in humans.
We report the results of using autologous TILs plus high-dose bolus interleukin 2 (IL-2), with or without the concomitant administration of cyclophosphamide, in the treatment of 86 consecutive patients with metastatic melanoma.
From May 1987 through December 1992, 86 patients (38 female and 48 male) with metastatic melanoma were treated (145 courses) with autologous TILs plus high-dose intravenous bolus IL-2 (720,000 IU/kg every 8 hours). TILs plus IL-2 were administered in two cycles separated by approximately 2 weeks. Two treatment cycles constituted one treatment course. Patients received a maximum of 15 doses of IL-2 per cycle given every 8 hours until grade 3 or 4 toxicity was reached that could not easily be reversed by standard supportive measures. All patients received concomitant medications to abrogate some of the side effects of IL-2 administration: acetaminophen (650 mg every 4 hours), indomethacin (50 mg every 8 hours), and ranitidine (150 mg every 12 hours). Fifty-seven of the 86 patients received a single intravenous dose of 25 mg/kg cyclophosphamide approximately 36 hours before receiving the first intravenous infusion of TILs plus IL-2. Six weeks after treatment, all known sites of disease were evaluated.
The overall objective response rate in these patients was 34% and was similar in patients receiving TILs and IL-2 alone (31%) or in conjunction with cyclophosphamide (35%). There was no significant difference in the objective response rate in patients whose therapy with high-dose IL-2 had failed (32%) compared with patients not previously treated with IL-2 (34%). The frequency of response to treatment was greater in those patients who were treated with TILs from younger cultures (P = .0001), TILs with shorter doubling times (P = .03), and TILs that exhibited higher lysis against autologous tumor targets (P = .0008). Patients who received TILs generated from subcutaneous tumor deposits had higher response rates (49%) compared with those receiving TILs from lymph nodes (17%; P = .006). There was one treatment-related death due to respiratory insufficiency.
Treatment with TILs and IL-2 with or without cyclophosphamide can result in objective responses in about one third of patients with metastatic melanoma. The side effects of treatment are transient in most patients, and this treatment can be safely administered. These results illustrate the potential value of immune lymphocytes for the treatment of patients with melanoma.
对源自各种组织学类型癌症患者的人肿瘤浸润淋巴细胞（TILs）的研究表明，人类存在针对已确诊恶性肿瘤的细胞免疫反应。
我们报告了使用自体TILs加超大剂量推注白细胞介素2（IL-2），联合或不联合环磷酰胺，治疗86例连续性转移性黑色素瘤患者的结果。
从1987年5月至1992年12月，86例（38例女性和48例男性）转移性黑色素瘤患者接受了（145个疗程）自体TILs加超大剂量静脉推注IL-2（每8小时720,000 IU/kg）治疗。TILs加IL-2分两个周期给药，间隔约2周。两个治疗周期构成一个疗程。患者每个周期最多接受15剂每8小时一次的IL-2，直至出现3级或4级毒性且无法通过标准支持措施轻易逆转。所有患者均接受辅助药物以减轻IL-2给药的一些副作用：对乙酰氨基酚（每4小时650 mg）、吲哚美辛（每8小时50 mg）和雷尼替丁（每12小时150 mg）。86例患者中有57例在首次静脉输注TILs加IL-2前约36小时接受了单次静脉注射25 mg/kg环磷酰胺。治疗6周后，对所有已知疾病部位进行评估。
这些患者的总体客观缓解率为34%，单独接受TILs和IL-2治疗的患者（31%）或联合环磷酰胺治疗的患者（35%）的缓解率相似。与未接受过IL-2治疗的患者（34%）相比，高剂量IL-2治疗失败的患者的客观缓解率（32%）无显著差异。用来自较年轻培养物的TILs治疗的患者（P = 0.0001）、TILs倍增时间较短的患者（P = 0.03）以及对自体肿瘤靶标表现出更高裂解活性的TILs治疗的患者（P = 0.0008）对治疗的反应频率更高。与接受来自淋巴结的TILs的患者（17%；P = 0.006）相比，接受来自皮下肿瘤沉积物的TILs的患者缓解率更高（49%）。有1例与治疗相关的死亡，死因是呼吸功能不全。
用TILs和IL-2联合或不联合环磷酰胺治疗可使约三分之一的转移性黑色素瘤患者获得客观缓解。大多数患者的治疗副作用是短暂的，且这种治疗可安全给药。这些结果说明了免疫淋巴细胞在治疗黑色素瘤患者中的潜在价值。
