Pujol J L, Gibney D J, Su J Q, Maksymiuk A W, Jett J R
University of Montpellier, France.
J Natl Cancer Inst. 1993 Nov 17;85(22):1844-50. doi: 10.1093/jnci/85.22.1844.
Chemotherapy, with or without radiotherapy, results in a 30%-40% complete response rate in small-cell lung cancer (SCLC), but approximately 90% of patients who have complete remission die within 2 years after relapse with chemoresistant disease. Randomized clinical studies of maintenance chemotherapy after complete response have failed to demonstrate survival advantage. However, studies have shown that the human cytokine interferon gamma (IFN-gamma) induces immune response in humans, including T-cell activation and expression of class II major histocompatibility complex (HLA-DR) and receptor for the Fc portion of immunoglobulin on monocytes. It has also been demonstrated that recombinant IFN-gamma (rIFN-gamma) induces immunomodulation and has antiproliferative activity.
In vivo effects of rIFN-gamma treatment were characterized by flow cytometric analysis of peripheral blood mononuclear cells in patients with SCLC who received rIFN-gamma as maintenance treatment.
After induction chemotherapy and radiotherapy, 100 patients who achieved a complete remission were randomly assigned to receive rIFN-gamma at a dose of 0.2 mg (4 x 10(6) units) once a day, subcutaneously, for 6 months, or observation only. In 31 patients, peripheral mononuclear cells were obtained prior to the study and at weeks 4, 8, and 12 for serial monitoring of immune response. By flow cytometric analysis, we identified the lymphocyte and monocyte populations using characteristic differences in electronic volume and right-angle scatter. In these populations, we determined the mean fluorescence channel after staining for CD14 (antigen expressed on monocytes), CD3 (antigen expressed on T lymphocytes), and HLA-DR (HLA class II expressed by monocytes and activated lymphocytes). To determine the number of Fc receptors per cell, an Fc receptor assay was performed using the monocyte cell line U937 as a standard.
At weeks 4, 8, and 12, expression of HLA-DR and Fc receptors on monocytes in patients who received rIFN-gamma was significantly higher than that in untreated patients, and the difference was statistically significant. The number of Fc receptors per monocyte consistently increased during the rIFN-gamma treatment and reached a fivefold elevation at week 12. There was no statistically significant difference in lymphocyte surface antigen expression between the treated and untreated groups.
The dose of rIFN-gamma used in this study resulted in immune stimulation in patients with SCLC who had complete remission after induction therapy. The in vivo immunomodulatory activity of rIFN-gamma in such patients is characterized by a strong monocyte activation but no significant alteration in T-cell activation.
化疗，无论是否联合放疗，在小细胞肺癌（SCLC）中可使30%-40%的患者获得完全缓解，但约90%完全缓解的患者在复发后2年内死于化疗耐药性疾病。完全缓解后进行维持化疗的随机临床研究未能证明其生存优势。然而，研究表明，人类细胞因子干扰素γ（IFN-γ）可在人体内诱导免疫反应，包括T细胞活化以及单核细胞上II类主要组织相容性复合体（HLA-DR）和免疫球蛋白Fc段受体的表达。也已证实重组干扰素γ（rIFN-γ）可诱导免疫调节并具有抗增殖活性。
通过对接受rIFN-γ作为维持治疗的SCLC患者外周血单个核细胞进行流式细胞术分析，来表征rIFN-γ治疗的体内效应。
诱导化疗和放疗后，100例获得完全缓解的患者被随机分配，分别接受剂量为0.2mg（4×10⁶单位）的rIFN-γ，每天皮下注射1次，共6个月，或仅进行观察。在31例患者中，在研究前以及第4、8和12周获取外周单个核细胞，用于连续监测免疫反应。通过流式细胞术分析，我们利用电子体积和直角散射的特征差异来识别淋巴细胞和单核细胞群体。在这些群体中，我们测定了用CD14（单核细胞上表达的抗原）、CD3（T淋巴细胞上表达的抗原）和HLA-DR（单核细胞和活化淋巴细胞表达的II类HLA）染色后的平均荧光通道。为了确定每个细胞的Fc受体数量，使用单核细胞系U937作为标准进行Fc受体测定。
在第4、8和12周，接受rIFN-γ治疗的患者单核细胞上HLA-DR和Fc受体的表达显著高于未治疗患者，差异具有统计学意义。在rIFN-γ治疗期间，每个单核细胞的Fc受体数量持续增加，在第12周达到了五倍的升高。治疗组和未治疗组之间淋巴细胞表面抗原表达没有统计学显著差异。
本研究中使用的rIFN-γ剂量在诱导治疗后获得完全缓解的SCLC患者中产生了免疫刺激作用。rIFN-γ在这类患者中的体内免疫调节活性表现为单核细胞的强烈活化，但T细胞活化无显著改变。
