Rosenberg S A, Yang J C, White D E, Steinberg S M
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ann Surg. 1998 Sep;228(3):307-19. doi: 10.1097/00000658-199809000-00004.
To determine the durability of complete responses in patients with metastatic melanoma or renal cancer treated with high-dose bolus interleukin-2 (IL-2) as well as the factors associated with the development of a complete response and the antigens mediating clinical responses.
A consecutive series of 409 patients with either metastatic melanoma or renal cancer who were treated with high-dose bolus IL-2 in the Surgery Branch, National Cancer Institute, between September 1985 and November 1996 have been analyzed with a median potential follow-up of 7.1 years. All patients were treated with 720,000 IU/kg administered by 15-minute intravenous infusions every 8 hours for up to 5 days as clinically tolerated per cycle. Two cycles constituted a treatment course. Tumor-infiltrating lymphocytes (TIL) from melanoma patients were used to clone the genes encoding the tumor antigens responsible for clinical responsiveness.
Thirty-three of 409 (8.1%) patients treated with high-dose bolus IL-2 achieved a complete response and 37 (9%) achieved a partial response. Complete regression was seen in 6.6% and 9.3% of patients with metastatic melanoma and renal cancer, respectively. Twenty-seven of these 33 completely responding patients (82%) remain in ongoing continuous complete response from 39 to more than 148 months from the onset of treatment. Tumor regressions were seen at virtually all organ sites. The absence of prior treatment with immunotherapy, the total dose of IL-2 administered, and the maximal rebound lymphocytosis after cessation of IL-2 correlated with achieving a complete response. Expression cloning techniques have identified a series of tumor antigens that are recognized by TIL grown from resected melanomas. These antigens are mainly melanoma/ melanocyte differentiation antigens, although mutated intracellular proteins can also serve as antigens.
Treatment with high-dose bolus IL-2 mediates complete cancer regression in approximately 8% of patients with metastatic renal cancer and melanoma. The great majority of these patients will enter durable complete regressions and appear to be cured of their metastatic cancer. Thus, immunotherapy with high-dose bolus IL-2 should be considered as initial therapy for appropriately selected patients with metastatic melanoma and renal cell cancer. Identification of the tumor antigens mediating clinical response is opening new therapeutic possibilities for cancer treatment.
确定接受大剂量推注白细胞介素-2（IL-2）治疗的转移性黑色素瘤或肾癌患者完全缓解的持久性，以及与完全缓解发生相关的因素和介导临床反应的抗原。
对1985年9月至1996年11月期间在美国国立癌症研究所外科分部接受大剂量推注IL-2治疗的409例转移性黑色素瘤或肾癌患者进行了连续分析，中位潜在随访时间为7.1年。所有患者每8小时静脉输注15分钟，剂量为720,000 IU/kg，根据临床耐受情况，每周期最多持续5天。两个周期构成一个疗程。使用黑色素瘤患者的肿瘤浸润淋巴细胞（TIL）克隆编码负责临床反应的肿瘤抗原的基因。
409例接受大剂量推注IL-2治疗的患者中，33例（8.1%）实现了完全缓解，37例（9%）实现了部分缓解。转移性黑色素瘤和肾癌患者的完全缓解率分别为6.6%和9.3%。这33例完全缓解的患者中有27例（82%）从治疗开始起持续完全缓解39至超过148个月。几乎所有器官部位都出现了肿瘤消退。未接受过免疫治疗、IL-2的总给药剂量以及停止IL-2后最大的淋巴细胞反应性增高与实现完全缓解相关。表达克隆技术已鉴定出一系列被从切除的黑色素瘤中培养的TIL识别的肿瘤抗原。这些抗原主要是黑色素瘤/黑色素细胞分化抗原，尽管突变的细胞内蛋白也可作为抗原。
大剂量推注IL-2治疗可使约8%的转移性肾癌和黑色素瘤患者实现癌症完全消退。这些患者中的绝大多数将进入持久的完全缓解状态，似乎已治愈转移性癌症。因此，对于适当选择的转移性黑色素瘤和肾细胞癌患者，大剂量推注IL-2免疫治疗应被视为初始治疗方法。鉴定介导临床反应的肿瘤抗原为癌症治疗开辟了新的治疗可能性。
