Yang J C, Topalian S L, Schwartzentruber D J, Parkinson D R, Marincola F M, Weber J S, Seipp C A, White D E, Rosenberg S A
Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Cancer. 1995 Aug 15;76(4):687-94. doi: 10.1002/1097-0142(19950815)76:4<687::aid-cncr2820760424>3.0.co;2-m.
Conjugation of polyethylene glycol to recombinant human interleukin-2 (IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG-IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life. In mice, one dose of PEG-IL-2 results in tumor regression comparable to that achieved with multiple bolus doses of IL-2. Based on these preclinical studies, a Phase I study with PEG-IL-2 was undertaken in patients with metastatic renal cell carcinoma (RCC) and melanoma. Then, to exploit the higher peak levels attained with IL-2 and the improved trough levels of PEG-IL-2, a combination regimen beginning with bolus IL-2 followed by low dose maintenance PEG-IL-2 was devised and tested for efficacy.
Patients with measurable metastatic melanoma or RCC were entered in a Phase I dose escalation trial of PEG-IL-2 given once a week by intravenous bolus. This trial then was repeated using a twice-a-week schedule. After determining the maximum tolerated dose (MTD) and a safe outpatient regimen for PEG-IL-2, a hybrid regimen combining an initial high dose IL-2 cycle followed by chronic maintenance with weekly PEG-IL-2 was devised. This regimen was compared with a standard regimen consisting of two cycles of high dose unconjugated IL-2 in a randomized prospective clinical trial.
When given by intravenous bolus once a week, the MTD of PEG-IL-2 was 12 million IU/m2, with toxicities similar to those of unconjugated IL-2. A twice-a-week schedule was less well tolerated. Of 28 patients given 32 treatment courses at varied dose levels, there were two partial responses and one minor response. A total of 124 patients with metastatic melanoma or RCC were randomized to either standard unconjugated IL-2 therapy or the hybrid regimen. There was no treatment-related mortality in either arm, and the use of PEG-IL-2 resulted in a significant decrease in the need for intensive-care-unit care. The response rates (partial response and complete response) for patients with RCC and melanoma were 19% and 15%, respectively, for IL-2 alone and 17% and 11%, respectively, for the IL-2 and PEG-IL-2 combination.
The combination of high dose IL-2 followed by PEG-IL-2 is a well tolerated regimen with significant activity against RCC and melanoma, but it shows no significant increase in antitumor activity compared with high dose IL-2 alone.
将聚乙二醇与重组人白细胞介素-2（IL-2）结合可产生一种化合物，即聚乙二醇修饰的IL-2（PEG-IL-2），它保留了IL-2的体外和体内活性，但循环半衰期明显延长。在小鼠中，一剂PEG-IL-2导致的肿瘤消退与多次推注IL-2所达到的效果相当。基于这些临床前研究，对转移性肾细胞癌（RCC）和黑色素瘤患者进行了PEG-IL-2的I期研究。然后，为了利用IL-2达到的较高峰值水平和PEG-IL-2改善的谷值水平，设计并测试了一种联合方案，该方案先推注IL-2，然后低剂量维持使用PEG-IL-2，以评估其疗效。
可测量的转移性黑色素瘤或RCC患者进入PEG-IL-2的I期剂量递增试验，每周静脉推注一次。然后使用每周两次的给药方案重复该试验。确定PEG-IL-2的最大耐受剂量（MTD）和安全的门诊治疗方案后，设计了一种联合方案，即先进行一个高剂量IL-2周期，然后长期维持使用每周一次的PEG-IL-2。在一项随机前瞻性临床试验中，将该方案与由两个高剂量未结合IL-2周期组成的标准方案进行比较。
当每周静脉推注一次时，PEG-IL-2的MTD为1200万IU/m²，毒性与未结合IL-2相似。每周两次的给药方案耐受性较差。在28例接受不同剂量水平32个疗程治疗的患者中，有2例部分缓解和1例轻微缓解。共有124例转移性黑色素瘤或RCC患者被随机分为标准未结合IL-2治疗组或联合方案组。两组均无治疗相关死亡病例，使用PEG-IL-2导致重症监护病房护理需求显著减少。RCC和黑色素瘤患者单独使用IL-2的缓解率（部分缓解和完全缓解）分别为19%和15%，IL-2与PEG-IL-2联合使用的缓解率分别为17%和11%。
高剂量IL-2后接PEG-IL-2的联合方案耐受性良好，对RCC和黑色素瘤具有显著活性，但与单独使用高剂量IL-2相比，抗肿瘤活性无显著增加。
