Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2 - Identification of the antigens mediating response
Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2 - Identification of the antigens mediating response
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DOI：
10.1097/00000658-199809000-00004
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发表时间：
1998-09-01
影响因子：
9
通讯作者：
Steinberg, SM
中科院分区：
文献类型：
--
作者：
Rosenberg, SA;Yang, JC;Steinberg, SM
目的探讨高剂量白介素-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，以及完全缓解的相关因素和介导临床反应的抗原。方法对1985年9月至1996年11月在美国国立癌症研究所外科分院接受大剂量IL-2治疗的409例转移性、黑色素瘤或肾癌患者进行连续分析，中位随访时间为7.1年。所有患者均接受720,000 IU/kg的治疗，每8小时15分钟静脉输注，根据临床耐受，每个周期最多5天。两个疗程构成一个疗程。来自黑色素瘤患者的肿瘤浸润淋巴细胞（TIL）被用于克隆编码负责临床反应的肿瘤抗原的基因。结果409例患者中33例（8.1%）获得完全缓解，37例（9%）获得部分缓解。转移性黑色素瘤和肾癌患者的完全消退分别为6.6%和9.3%。在这33名完全缓解的患者中，有27名（82%）在治疗开始后的39至148个月内保持持续的完全缓解。几乎所有器官部位均可见肿瘤消退。先前未接受免疫治疗、给予IL-2的总剂量以及停止使用IL-2后的最大反弹淋巴细胞增多与获得完全缓解相关。表达克隆技术已经鉴定出一系列肿瘤抗原，这些抗原主要是黑色素瘤/黑素细胞分化抗原，尽管突变的细胞内蛋白也可以作为抗原。结论：在大约8%的转移性肾癌和黑色素瘤患者中，大剂量IL-2治疗可使肿瘤完全消退。这些患者中的绝大多数将进入持久的完全消退，并似乎治愈了转移性癌症。因此，应将大剂量IL-2免疫治疗作为初始治疗；适当选择转移性黑色素瘤和肾细胞癌患者，确定肿瘤抗原介导临床反应，为癌症治疗开辟了新的治疗可能性。
Objective 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.Methods 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.Results 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.Conclusions 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 io;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.