Kirkwood John M, Richards Thomas, Zarour Hassane M, Sosman Jeffrey, Ernstoff Marc, Whiteside Theresa L, Ibrahim Joseph, Blum Ronald, Wieand Samuel, Mascari Ruth
Department of Medicine, University of Pittsburgh, Pennsylvania, USA.
Cancer. 2002 Sep 1;95(5):1101-12. doi: 10.1002/cncr.10775.
The clinical antitumor activity of recombinant interferon alpha2b (IFNalpha2b) has been well documented in patients with advanced and high-risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNalpha2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients).
This study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNalpha2b at a range of concentrations in vitro.
Baseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNalpha2b treatment was observed and was associated with IFNalpha2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM-1) were modulated by exposure to IFNalpha2b in a dose dependent manner. Blood natural killer (NK) cell function, T-cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes.
These data demonstrate changes in immunologic parameters associated with IFNalpha2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNalpha2b and T-cell response to specific antigens of melanoma.
重组干扰素α2b（IFNα2b）在晚期和高危黑色素瘤患者中的临床抗肿瘤活性已有充分记录；然而，其作用机制仍存在推测。试验E2690评估了IFNα2b在高剂量治疗期间（高剂量组；n = 51例患者）和低剂量治疗期间（低剂量组；n = 54例患者）相对于标准观察（观察组；n = 43例患者）的体内免疫调节作用。
本研究在高剂量组、低剂量组和观察组中，于1个月、3个月和12个月时评估外周血淋巴细胞（PBL）的表型标志物和细胞毒性功能，并检查PBL或肿瘤中观察到的变化与治疗剂量和疾病结局之间的相关性。对肿瘤活检样本进行体外不同浓度IFNα2b的反应研究。
基线血液表型和功能检测无法预测疾病结局；然而，观察到IFNα2b治疗可调节这些免疫检测，且与IFNα2b剂量相关。肿瘤细胞II类主要组织相容性抗原表达（人类白细胞/淋巴细胞抗原DR）和黏附分子表达（ICAM-1）通过暴露于IFNα2b呈剂量依赖性调节。高剂量组患者早期调节血液自然杀伤（NK）细胞功能、T细胞功能和亚群分布，低剂量组患者后期调节。这些研究中测试的变量均未预测无复发生存率。研究的患者数量可能少于检测潜在临床显著变化所需的数量。
这些数据表明与IFNα2b治疗和剂量相关的免疫参数变化，这可能解释了该治疗方式临床疗效差异的部分原因。目前的结果还表明需要进一步研究IFNα2b的更新分子中间体以及T细胞对黑色素瘤特定抗原的反应。
