Schiller J H, Hank J A, Khorsand M, Storer B, Borchert A, Huseby-Moore K, Burns D, Wesly O, Albertini M R, Wilding G, Sondel P M
University of Wisconsin Comprehensive Cancer Center, Departments of Human Oncology and Medicine, Madison, Wisconsin 53792, USA.
Clin Cancer Res. 1996 Feb;2(2):319-30.
Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects of the combination. Thirty-four patients with incurable cancers received 2.5, 5, or 10 microgram/kg GM-CSF s.c. either before or concurrently with 1.5 or 3.0 million units/m2/day IL-2. The most common laboratory and clinical side effects included an elevation of the total WBC or eosinophil count due to GM-CSF, and constitutional symptoms due to IL-2. Grade 3 or 4 toxicities included hypotension, thrombocytopenia, elevations in aspartate aminotransferase or bilirubin, renal toxicity, gastrointestinal hemorrhage, arrhythmia, and constitutional symptoms. Two patients receiving 5.0 microgram/kg GM-CSF plus concurrent 3.0 million units IL-2 experienced dose-limiting grade 3 or 4 neurological toxicity, which reversed almost completely. An increase in the serum-soluble IL-2 alpha chain receptor was observed with administration of GM-CSF, IL-2, or the combination. IL-2 therapy enhanced lymphokine-activated killer activity, antibody-dependent cellular cytotoxicity, and lymphocyte activation, with increased CD16 and CD56 expression. GM-CSF increased expression of human leukocyte antigen DR on peripheral blood monocytes and decreased surface expression of CD16 on circulating monocytes and polymorphonuclear cells. Lymphokine-activated killer activity and CD16 expression on monocytes and lymphocytes and CD56 expression on lymphocytes were significantly lower in patients receiving GM-CSF simultaneously with IL-2 than in patients receiving the sequential treatment. Antitumor activity was observed in the lungs of four of eight renal cell carcinoma patients with pulmonary metastases treated with concurrent GM-CSF and IL-2. Although no or minimal shrinkage was observed in the patients' large primary tumors, these results warrant further study. The recommended initial Phase II dose and schedule is 1.25 microgram/kg/day GM-CSF, given concurrently with 1.5 million Roche units/m2/day (4.5 x 10(6) international units/m2/day) IL-2, with subsequent escalation of GM-CSF to 2.5 microgram/kg/day after careful observation for toxicities.
白细胞介素2（IL-2）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）分别是淋巴细胞和粒细胞/巨噬细胞系列的激活剂。我们开展了一项1B期试验，以确定最大耐受剂量并评估联合用药的免疫效果。34例无法治愈的癌症患者接受了2.5、5或10微克/千克的GM-CSF皮下注射，注射时间为1.5或3.0百万单位/平方米/天的IL-2之前或同时。最常见的实验室和临床副作用包括GM-CSF导致的白细胞总数或嗜酸性粒细胞计数升高，以及IL-2导致的全身症状。3级或4级毒性包括低血压、血小板减少、天冬氨酸转氨酶或胆红素升高、肾毒性、胃肠道出血、心律失常和全身症状。两名接受5.0微克/千克GM-CSF加同时3.0百万单位IL-2治疗的患者出现了剂量限制性3级或4级神经毒性，但几乎完全逆转。在给予GM-CSF、IL-2或联合用药后，观察到血清可溶性IL-2α链受体增加。IL-2治疗增强了淋巴因子激活的杀伤活性、抗体依赖性细胞毒性和淋巴细胞激活，同时CD16和CD56表达增加。GM-CSF增加了外周血单核细胞上人类白细胞抗原DR的表达，并降低了循环单核细胞和多形核细胞上CD16的表面表达。与接受序贯治疗的患者相比，同时接受GM-CSF和IL-2治疗的患者中，单核细胞和淋巴细胞上的淋巴因子激活的杀伤活性以及CD16表达和淋巴细胞上的CD56表达显著降低。在8例接受GM-CSF和IL-2联合治疗的肺转移肾细胞癌患者中，有4例在肺部观察到抗肿瘤活性。尽管在患者的大的原发性肿瘤中未观察到缩小或仅有极小的缩小，但这些结果值得进一步研究。推荐的II期初始剂量和方案为1.25微克/千克/天的GM-CSF，与1.5百万罗氏单位/平方米/天（4.5×10⁶国际单位/平方米/天）的IL-2同时给药，在仔细观察毒性后，随后将GM-CSF剂量增至2.5微克/千克/天。
