Hjelm Skog A, Ragnhammar P, Fagerberg J, Frödin J, Goldinger M, Koldestam H, Liljefors M, Nilsson B, Shetye J, Wersäll P, Mellstedt H
Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Stockholm, Sweden.
Cancer Immunol Immunother. 1999 Nov;48(8):463-70. doi: 10.1007/s002620050623.
Granulocyte/macrophage-colony-stimulating factor (GM-CSF) has previously been indicated to enhance the therapeutic effect of the anti-colorectal carcinoma mAb17-1A as well as to augment in vivo immune effector functions. In vitro interleukin-2 (IL-2) augmented GM-CSF-induced antibody-dependent cellular cytotoxicity, a mechanism considered to be of significance for the therapeutic effect of mAb. A treatment regimen was elaborated that combined mAb17-1A (400 mg at day 3 of a 10-day treatment cycle) with the simultaneous administration of GM-CSF (250 microgram/m(2) once daily) and IL-2 (2.4 x 10(6) U/m(2) twice daily) for 10 days. The treatment cycle was repeated once a month. Twenty patients with advanced colorectal carcinoma were included in the study. One patient obtained a partial remission and 2 patients stable disease for 7 and 4 months respectively. The median survival time from the start of mAb therapy was 8 months. Owing to allergic reactions, the planned mAb17-1A dose had to be reduced by repeated infusions. At the fourth treatment cycle only 25% received the planned mAb dose. In 3 patients the GM-CSF and IL-2 dose was reduced because of side-effects. The subjective tolerability of the treatment was considered good or acceptable in more than 80% of the patients. The increment in white blood cell subsets induced by the cytokines decreased by increasing number of courses. This particular regimen did not augment the therapeutic effect of mAb17-1A anticipated from in vitro data but rather hampered the clinical effect of the antibody. The reason for this is not clear but a possibility might be the induction of immune suppression in vivo resulting from an impaired human anti-(mouse Ab) and anti-idiotypic antibody response as well as antibody-dependent cellular cytotoxicity, on the basis of a comparison of mAb17-1A/GM-CSF/IL-2- and mAb17-1A/GM-CSF-treated patients.
粒细胞/巨噬细胞集落刺激因子（GM-CSF）此前已被证明可增强抗结肠直肠癌单克隆抗体17-1A的治疗效果，并增强体内免疫效应功能。在体外，白细胞介素-2（IL-2）增强了GM-CSF诱导的抗体依赖性细胞毒性，这一机制被认为对单克隆抗体的治疗效果具有重要意义。制定了一种治疗方案，将单克隆抗体17-1A（在10天治疗周期的第3天给予400毫克）与同时给予GM-CSF（250微克/平方米，每日一次）和IL-2（2.4×10⁶单位/平方米，每日两次）联合使用10天。治疗周期每月重复一次。20例晚期结肠直肠癌患者纳入研究。1例患者获得部分缓解，2例患者病情稳定，分别持续7个月和4个月。从单克隆抗体治疗开始的中位生存时间为8个月。由于过敏反应，计划的单克隆抗体17-1A剂量不得不通过重复输注而降低。在第四个治疗周期，只有25%的患者接受了计划的单克隆抗体剂量。3例患者因副作用而降低了GM-CSF和IL-2的剂量。超过80%的患者认为该治疗的主观耐受性良好或可接受。细胞因子诱导的白细胞亚群增加量随着疗程数的增加而减少。这种特定方案并未增强体外数据预期的单克隆抗体17-1A的治疗效果，反而阻碍了抗体的临床效果。其原因尚不清楚，但一种可能性可能是基于对单克隆抗体17-1A/GM-CSF/IL-2治疗患者和单克隆抗体17-1A/GM-CSF治疗患者的比较，体内因人类抗（鼠抗体）和抗独特型抗体反应受损以及抗体依赖性细胞毒性而导致免疫抑制的诱导。
