PROSPECTIVE RANDOMIZED TRIAL OF HIGH-DOSE INTERLEUKIN-2 ALONE OR IN CONJUNCTION WITH LYMPHOKINE-ACTIVATED KILLER-CELLS FOR THE TREATMENT OF PATIENTS WITH ADVANCED CANCER
PROSPECTIVE RANDOMIZED TRIAL OF HIGH-DOSE INTERLEUKIN-2 ALONE OR IN CONJUNCTION WITH LYMPHOKINE-ACTIVATED KILLER-CELLS FOR THE TREATMENT OF PATIENTS WITH ADVANCED CANCER
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DOI：
10.1093/jnci/85.8.622
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发表时间：
1993-04-21
影响因子：
10.3
通讯作者：
STEINBERG, SM
中科院分区：
文献类型：
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作者：
ROSENBERG, SA;LOTZE, MT;STEINBERG, SM
研究背景：白细胞介素-2 （IL-2）单独或联合淋巴因子激活杀手（LAK）细胞治疗已被证明可介导晚期癌症患者的疾病消退。目的：这项前瞻性随机试验旨在确定LAK细胞联合大剂量IL-2治疗是否会改变晚期癌症患者的反应和生存率，与单独使用IL-2治疗相比。方法：181例标准治疗无效或无有效治疗方法的转移性癌症患者接受单独大剂量IL-2或LAK细胞加IL-2治疗。两组均按相同的治疗方案给予相同剂量的IL-2。根据患者的耐受性，省略IL-2剂量。在181名患者中，97名患有肾细胞癌，54名患有黑色素瘤。结果：中位潜在随访时间为63.2个月。在85名接受IL-2 + LAK细胞治疗的可评估患者中，有10人完全缓解，而在79名单独接受IL-2治疗的患者中，只有4人完全缓解。分别有14个和12个部分反应。7例患者在50-66个月时仍有完全缓解。IL-2 + LAK细胞的36个月精算生存率为31%，而单独IL-2的生存率为17%（双侧P值[P2] = 0.089）。与单独接受IL-2的黑色素瘤患者相比，接受IL-2 + LAK细胞治疗的黑色素瘤患者生存率有改善的趋势（24个月生存率：32%对15%；48个月生存率：18%对4%；P2 = 0.64）。单独接受IL-2治疗的26例黑色素瘤患者无一生还；接受IL-2 + LAK细胞治疗的28例患者中有5例存活，3例持续完全缓解。两个治疗组的肾细胞癌患者生存率无差异。治疗相关死亡6例（3.3%）；3例为心肌梗死。其他毒性作用通过停止使用IL-2而消失。许多毒性作用与IL-2诱导的血管通透性增加有关。结论：一些转移性癌症患者单独使用高剂量IL-2或与LAK细胞联合使用时，缓解期延长。我们的研究结果表明，当黑色素瘤患者与LAK细胞一起给予IL-2时，生存率有增加的趋势，但在肾细胞癌患者中没有观察到这种趋势。随着这些研究的继续，人们正在努力开发使用肿瘤浸润淋巴细胞（TIL）和基因修饰TIL的改进免疫疗法。
Background: Treatment using interleukin-2 (IL-2) alone or in conjunction with lymphokine-activated killer (LAK) cells has been shown to mediate disease regression in selected patients with advanced cancer. Purpose: This prospective randomized trial was designed to determine whether the administration of LAK cells in conjunction with high-dose IL-2 alters response and survival rates, compared with those for IL-2 alone, in patients with advanced cancer. Methods: The 181 patients who had metastatic cancer that had failed to respond to standard therapy or who had disease for which no effective therapy existed received treatment with high-dose IL-2 alone or with LAK cells plus IL-2. Both treatment groups were to receive the same dose of IL-2 administered according to the same schedule. IL-2 doses were omitted depending on the tolerance of the patient. Of the 181 patients, 97 had renal cell cancer and 54 had melanoma. Results: Median potential follow-up was 63.2 months. There were 10 complete responses among the 85 assessable patients who received IL-2 plus LAK cells, compared with four among the 79 who received IL-2 alone. There were 14 and 12 partial responses, respectively. Complete response continues in seven patients at 50-66 months. The 36-month actuarial survival with IL-2 plus LAK cells was 31%, compared with 17% with IL-2 alone (two-sided P value [P2] = .089). A trend toward improved survival was seen for patients with melanoma who received IL-2 plus LAK cells, compared with those who received IL-2 alone (24-month survival: 32% versus 15%; 48-month survival: 18% versus 4%; P2 = .64). None of 26 patients with melanoma who received IL-2 alone are alive; five of 28 who received IL-2 plus LAK cells are alive, and three continue in complete response. No difference in survival was seen in patients with renal cell cancer in the two treatment groups. There were six treatment-related deaths (3.3%); three were due to myocardial infarction. Other toxic effects resolved by discontinuation of IL-2. Many toxic effects were related to increased vascular permeability induced by IL-2. Conclusions: Some patients with metastatic cancer have prolonged remission when they are treated with high-dose IL-2 alone or in conjunction with LAK cells. Our results suggest a trend toward increased survival when IL-2 is given with LAK cells in patients with melanoma, but no trend was observed for patients with renal cell cancer. Implications: As these studies continue, efforts are underway to develop improved immunotherapies using tumor-infiltrating lymphocytes (TIL) and gene-modified TIL.