Everse L A, Bernsen M R, Dullens H F, Den Otter W
Department of Functional Morphology, Utrecht University, The Netherlands.
J Exp Ther Oncol. 1996 Jul;1(4):231-6.
The extremely different administration schedules that are used in testing recombinant interleukin-2 (rIL-2) therapies for cancer may account for the extreme variation in efficacy reported in various studies in animal models. A major point may be the variation of the time interval between tumor transplantation and rIL-2 therapy. We hypothesized that administration of rIL-2 before the immune system has mounted a specific cellular reaction against the tumor (associated antigens) might result in lesser efficacies than later rIL-2 administration. This hypothesis was tested in DBA/2 mice bearing a syngeneic SL2 lymphoma. When 7000 IV/day rIL-2 was administered to tumor-bearing mice for 5 consecutive days starting on day 1, 3, 4, 5, or 6 after tumor inoculation, the survival curve of the mice did not significantly differ from that of diluent-treated mice. In contrast, a significant difference was observed when treatment was begun on day 7, 8, 9, 10, or 12 (p < or = 0.004). rIL-2 therapies begun on day 9 or 10 were most effective, curing up to 80% of mice treated, despite there being an enormous burden of disseminated tumor present at that time (1-4% of the total body weight). When rIL-2 was administered for fewer than 5 consecutive days, beginning on day 10, the efficacy of the therapy dropped radically (p < or = 0.055). Involvement of a specific anti-tumor reaction was also tested. All mice that were cured of the tumor as a result of rIL-2 therapy proved to be specifically immune to the SL2 tumor. Furthermore, day 10-14 administration of rIL-2 was completely ineffective in CD4(+)-cell depleted mice (p = 0.0116 vs. rIL-2 therapy in non-depleted mice). Together, this implies that this form of rIL-2 therapy is mediated by tumor-specific T-cells. As a whole, these results indicate that T-cell mediated rIL-2 therapy of cancer in animal models is sensitive to the time when the rIL-2 is administered and to the length of time for which the rIL-2 is given. This should be taken into account when planning new therapy protocols and when analyzing published data.
在测试用于癌症治疗的重组白细胞介素 -2（rIL -2）疗法时所采用的极为不同的给药方案，可能是导致各种动物模型研究中所报道的疗效存在极大差异的原因。一个关键因素可能是肿瘤移植与rIL -2治疗之间时间间隔的变化。我们推测，在免疫系统针对肿瘤（相关抗原）产生特异性细胞反应之前给予rIL -2，其疗效可能低于在这之后给予rIL -2的疗效。这一假设在携带同基因SL2淋巴瘤的DBA/2小鼠中进行了验证。当从肿瘤接种后的第1、3、4、5或6天开始，对荷瘤小鼠连续5天每天静脉注射7000单位的rIL -2时，小鼠的生存曲线与用稀释剂处理的小鼠相比没有显著差异。相比之下，当从第7、8、9、10或12天开始治疗时，观察到了显著差异（p≤0.004）。从第9天或第10天开始的rIL -2疗法最为有效，能治愈高达80%接受治疗的小鼠，尽管此时存在大量已扩散的肿瘤（占总体重的1 - 4%）。当从第10天开始连续给予rIL -2的天数少于5天时，治疗效果急剧下降（p≤0.055）。还对特异性抗肿瘤反应的参与情况进行了测试。所有因rIL -2治疗而治愈肿瘤的小鼠都被证明对SL2肿瘤具有特异性免疫。此外，在CD4(+)细胞耗竭的小鼠中，第10 - 14天给予rIL -2完全无效（与未耗竭小鼠的rIL -2治疗相比，p = 0.0116）。综合来看，这意味着这种形式的rIL -2治疗是由肿瘤特异性T细胞介导的。总体而言，这些结果表明，在动物模型中，T细胞介导的rIL -2癌症治疗对rIL -2的给药时间以及给药时长敏感。在规划新的治疗方案和分析已发表的数据时应考虑到这一点。
