Meropol N J, Porter M, Blumenson L E, Lindemann M J, Perez R P, Vaickus L, Loewen G M, Creaven P J, Wilkes K A, Giedlin M A, Caligiuri M A
Divisions of Medicine, Molecular Medicine, Molecular Immunology, and Biostatistics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Clin Cancer Res. 1996 Apr;2(4):669-77.
We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2. Adult cancer patients received a single daily s.c. injection of IL-2 as outpatients for 90 consecutive days. Cohorts of four to nine patients were treated at escalating IL-2 dose levels until the maximum tolerated dose (MTD) was defined. Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated. Thirty-eight patients were treated at seven IL-2 dose levels ranging from 0.4 to 1.75 million International Units (mIU)/m2 daily. The MTD was 1.25 mIU/m2, with constitutional side effects, vomiting, and hyperglycemia dose limiting. Severe toxicity did not occur at or below the MTD, although mild local skin reaction and mild constitutional side effects were common. Objective tumor regressions were not observed during this Phase I trial. Low-dose IL-2 resulted in natural killer (NK) cell (CD3(-) CD56(+)) expansion at all dose levels. This effect was dose dependent (P < 0.01), ranging from a 154 to 530% increase over baseline. Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks of therapy. As predicted by in vitro studies of IL-2 receptor structure-activity relationships, the subset of NK cells that constitutively express high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more profound dose-dependent expansion, with increases ranging from 368 to 2763% (P = 0.015). NK expansion occurred at peak IL-2 levels <10 pM (2.3 IU/ml). Three patients developed nonneutralizing anti-IL-2 antibodies. Thus, we concluded that selective expansion of NK cells may be achieved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.
我们旨在确定每日皮下注射低剂量白细胞介素（IL）-2的毒性和免疫效应。成年癌症患者作为门诊病人连续90天接受每日一次皮下注射IL-2。以四至九名患者为一组，逐步提高IL-2剂量水平进行治疗，直至确定最大耐受剂量（MTD）。对外周血单个核细胞进行表型分析、检测IL-2血清水平以及检测抗IL-2抗体的存在情况。38名患者在七个IL-2剂量水平接受治疗，剂量范围为每日0.4至175万国际单位（mIU）/m²。MTD为1.25 mIU/m²，全身副作用、呕吐和高血糖为剂量限制性因素。在MTD及以下剂量未出现严重毒性，不过轻度局部皮肤反应和轻度全身副作用较为常见。在该I期试验期间未观察到客观肿瘤消退情况。低剂量IL-2在所有剂量水平均导致自然杀伤（NK）细胞（CD3(-)CD56(+)）扩增。这种效应呈剂量依赖性（P < 0.01），较基线水平增加154%至530%。NK细胞水平在6至8周达到峰值，并在治疗12周内持续保持。正如对IL-2受体结构-活性关系的体外研究所预测的，组成性表达高亲和力IL-2受体（CD3(-)CD56(bright+)）的NK细胞亚群显示出更显著的剂量依赖性扩增，增加幅度为368%至2763%（P = 0.015）。NK细胞扩增发生在IL-2峰值水平<10 pM（2.3 IU/ml）时。三名患者产生了非中和性抗IL-2抗体。因此，我们得出结论，每日皮下注射低剂量IL-2可在体内实现NK细胞的选择性扩增，且毒性极小。
