Pautier Patricia, Locher Clara, Robert Caroline, Deroussent Alain, Flament Caroline, Le Cesne Axel, Rey Annie, Bahleda Ratislav, Ribrag Vincent, Soria Jean-Charles, Vassal Gilles, Eggermont Alexander, Zitvogel Laurence, Chaput Nathalie, Paci Angelo
Département de Médecine; Institut de Cancérologie Gustave Roussy; Villejuif, France.
Oncoimmunology. 2013 Feb 1;2(2):e23079. doi: 10.4161/onci.23079.
Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation.
甲磺酸伊马替尼（IM）是一种蛋白酪氨酸激酶小分子抑制剂。除了对恶性细胞有直接作用外，有人提出IM可能激活自然杀伤（NK）细胞，从而发挥免疫调节功能。在临床前研究中，当IM与白细胞介素-2（IL-2，一种增强NK细胞功能的细胞因子）联合使用时，观察到抗肿瘤反应有所改善。本研究的目的是确定在IM固定剂量为400mg时，IL-2与IM联合使用的最大耐受剂量（MTD）、IM和IL-2的药代动力学，以及这种免疫治疗方案对晚期肿瘤患者的毒性和临床疗效。治疗方案包括在IM治疗开始前21天至整个第一个IM疗程（从第-21天至第14天）给予50mg/天的环磷酰胺，14天（第1天至第14天）给予400mg/天的IM，并从第10天至第14天联合递增剂量的IL-2（3、6、9和12 MIU/天）。该治疗方案每三周对17名患者进行一次给药。联合治疗的常见副作用为轻至中度，包括发热、寒战、疲劳、恶心和肝酶升高。IL-2剂量水平II（6 MIU/天）被确定为MTD，其剂量限制性毒性包括全身毛细血管渗漏综合征、疲劳和厌食。药代动力学研究表明，当IM与IL-2同时给药时，IM及其主要代谢产物CGP74588的曲线下面积和最大浓度显著增加。相反，IM并未调节IL-2的药代动力学。未观察到客观反应。获得的最佳反应为17例中的8例病情稳定（中位持续时间：12周）。最后，IL-2增强了IM及其代谢产物的浸润。在表达IM靶点的肿瘤中，IM（400mg/天）与IL-2（6 MIU/天）联合使用值得进一步研究。
