Verra N, Jansen R, Groenewegen G, Mallo H, Kersten M J, Bex A, Vyth-Dreese F A, Sein J, van de Kasteele W, Nooijen W J, de Waal M, Horenblas S, de Gast G C
Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Br J Cancer. 2003 May 6;88(9):1346-51. doi: 10.1038/sj.bjc.6600915.
The purpose of the study was to determine toxicity, efficacy and immunologic effects of concurrent subcutaneous injections of low-dose interleukin-2 (LD-IL-2), granulocyte-monocyte colony-stimulating factor (GM-CSF) and interferon-alpha 2b (IFNalpha) in progressive metastatic renal cell carcinoma. In a multicentre phase II study, 59 evaluable patients received two to six cycles of subcutaneous IL-2 (4 mIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFNalpha (5 mIU flat(-1)) for 12 days per 3 weeks with evaluation after every two cycles. Cycles were repeated in responding or stable patients. Data were analysed after a median of 30 months follow-up (range 16-48 months). In 42 patients, the immunologic response was studied and related to response and survival. The main toxicity were flu-like symptoms, malaise and transient liver enzyme elevations, necessitating IL-2 reduction to 2 mIU m(-2) in 29 patients, which should be considered the maximal tolerable dose. The response was 24% (eight out of 34, three complete response (CR), five partial response (PR)) in patients with metachronic metastases and 12% (three out of 25, 2CR, 1PR) in patients with synchronic metastases. Overall response was 19% (11 out of 59). Median survival was 9.5 months. All tested patients showed expansion and/or activation of lymphocytes, T cells and subsets, NK cells, eosinophils and monocytes. Pretreatment HLA-DR levels on monocytes and number of CD4(+)HLA-DR(+) cells correlated with response. Pretreatment number of CD4(+)HLA-DR(+) cells and postimmunotherapy levels of lymphocytes, CD3(+), CD4(+) and CD8(+) T cells, but not of NK or B cells, correlated with prolonged survival. Immunotherapy with concurrent subcutaneous GM-CSF, LD-IL-2 and IFNalpha has limited toxicity, can be given as outpatient treatment and can induce durable CR. Response and survival with this form of immunotherapy seem to be more dependent on expansion/activation of T cells than of NK cells.
本研究的目的是确定在进展期转移性肾细胞癌中同时皮下注射低剂量白细胞介素-2（LD-IL-2）、粒细胞-单核细胞集落刺激因子（GM-CSF）和干扰素-α2b（IFNα）的毒性、疗效及免疫效应。在一项多中心II期研究中，59例可评估患者每3周接受两至六个周期的皮下注射IL-2（4 mIU m⁻²）、GM-CSF（2.5 μg kg⁻¹）和IFNα（5 mIU固定剂量⁻¹），持续12天，每两个周期后进行评估。对有反应或病情稳定的患者重复进行周期治疗。在中位随访30个月（范围16 - 48个月）后对数据进行分析。对42例患者研究了免疫反应，并将其与反应和生存情况相关联。主要毒性为流感样症状、不适和短暂的肝酶升高，29例患者需要将IL-2剂量减至2 mIU m⁻²，这应被视为最大耐受剂量。异时转移患者的反应率为24%（34例中的8例，3例完全缓解（CR），5例部分缓解（PR）），同时转移患者的反应率为12%（25例中的3例，2例CR，1例PR）。总体反应率为19%（59例中的11例）。中位生存期为9.5个月。所有受试患者均表现出淋巴细胞、T细胞及其亚群、NK细胞、嗜酸性粒细胞和单核细胞的扩增和/或激活。单核细胞上的预处理HLA-DR水平和CD4⁺HLA-DR⁺细胞数量与反应相关。预处理的CD4⁺HLA-DR⁺细胞数量以及免疫治疗后淋巴细胞、CD3⁺、CD4⁺和CD8⁺T细胞（而非NK或B细胞）的水平与生存期延长相关。同时皮下注射GM-CSF、LD-IL-2和IFNα进行免疫治疗毒性有限，可作为门诊治疗给药，且可诱导持久的CR。这种免疫治疗形式的反应和生存似乎更依赖于T细胞而非NK细胞的扩增/激活。
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