Apte Sachin M, Vadhan-Raj Saroj, Cohen Lorenzo, Bassett Roland L, Gordon Ilyssa O, Levenback Charles F, Ramirez Pedro T, Gallardo Stacie T, Patenia Rebecca S, Garcia Michael E, Iyer Revathy B, Freedman Ralph S
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
J Transl Med. 2006 Apr 7;4:16. doi: 10.1186/1479-5876-4-16.
Monocyte/macrophages (MO/MA), a polymorphic population of innate immune cells, have the potential to mediate antitumor effects, and may also contribute to protumor effects. A priming and post-chemotherapy schedule of the myeloid cell mobilizing and immune stimulatory growth factor, granulocyte monocyte stimulating factor (GM-CSF, Leukine) and the MO/MA activating cytokine recombinant interferon gamma 1b (rIFN-gamma1b, Actimmune) has been developed. The pre- and post-chemotherapy design is based upon known in vivo kinetics and immune modulatory effects of these molecules. Carboplatin (Paraplatin) was selected as the cornerstone of treatment of epithelial ovarian cancer (EOC).
We studied hematopoietic and immunologic effects of GM-CSF and rIFN-gamma1b before and after carboplatin in patients with recurrent EOC. Potentially chemotherapy-sensitive patients with recurrent measurable tumors received subcutaneous GM-CSF (starting at 400 mug/day) for 7 days plus subcutaneous rIFN-gamma1b (100 mug) on days 5 and 7, before and after intravenous carboplatin (area under the curve of 5). We performed standard hematologic assessment and monitored monocyte (MO), dendritic cell, major cell subset counts, and antibody-dependent cell-mediated cytotoxicity (ADCC) against a Her2neu+ tumor cell line, as well as selected plasma inflammatory cytokine, chemokine and growth factor levels.
Our analysis comprised only the first 3 months of treatment in the initial 25 patients. Relative to pretreatment baseline values, white blood cell, neutrophil, MO, and eosinophil counts increased (P <or= .001 for each); the proportion of platelets increased 9 days after the second (P <or= .002) and third (P <or= .04) carboplatin treatments; and the number of cells in the activated MO subsets CD14+HLA-DR+, CD14+CD64+, and CD14+CXCR3+ increased (P <or= .04 for each); plasma levels of the proangiogenic interleukins 1alpha, 6, and 8 were lower (P <or= .03 for each); M-CSF, a product of activated MO/MA, was increased on day 9 (P = .007); and GM-CSF was increased in plasma after GM-CSF administration (P <or= .04). Quality of life measurements were reduced during the GM-CSF/IFN-gamma1b cycle while recovering at pre-chemotherapy baseline for FACT-G scores only.
A novel regimen of GM-CSF plus IFN-gamma1b administered to 25 EOC patients receiving carboplatin increased myeloid cells, platelets and total activated MO populations during the initial 3 months; however, ADCC responses were not consistently enhanced during this period.
单核细胞/巨噬细胞（MO/MA）是先天性免疫细胞的多态性群体，具有介导抗肿瘤作用的潜力，也可能有助于肿瘤的发生发展。已制定了髓样细胞动员和免疫刺激生长因子、粒细胞-单核细胞刺激因子（GM-CSF，乐复能）以及MO/MA激活细胞因子重组干扰素γ1b（rIFN-γ1b，干复津）的预化疗和化疗后给药方案。化疗前后的设计基于这些分子已知的体内动力学和免疫调节作用。卡铂（顺铂）被选为上皮性卵巢癌（EOC）治疗的基石。
我们研究了复发性EOC患者在卡铂治疗前后GM-CSF和rIFN-γ1b对造血和免疫的影响。患有复发性可测量肿瘤且可能对化疗敏感的患者在静脉注射卡铂（曲线下面积为5）前后，皮下注射GM-CSF（起始剂量为400μg/天），共7天，并在第5天和第7天皮下注射rIFN-γ1b（100μg）。我们进行了标准血液学评估，并监测单核细胞（MO）、树突状细胞、主要细胞亚群计数，以及针对Her2neu+肿瘤细胞系的抗体依赖性细胞介导的细胞毒性（ADCC），以及选定的血浆炎症细胞因子、趋化因子和生长因子水平。
我们的分析仅包括最初25例患者治疗的前3个月。与治疗前基线值相比，白细胞、中性粒细胞、MO和嗜酸性粒细胞计数增加（每项P≤0.001）；血小板比例在第二次（P≤0.002）和第三次（P≤0.04）卡铂治疗后9天增加；活化的MO亚群CD14+HLA-DR+、CD14+CD64+和CD14+CXCR3+中的细胞数量增加（每项P≤0.04）；促血管生成的白细胞介素1α、6和8的血浆水平较低（每项P≤0.03）；活化的MO/MA产物M-CSF在第9天增加（P = 0.007）；GM-CSF给药后血浆中GM-CSF增加（P≤0.04）。在GM-CSF/IFN-γ1b周期中，生活质量测量值降低，而仅FACT-G评分在化疗前基线恢复。
对25例接受卡铂治疗的EOC患者给予GM-CSF加IFN-γ1b的新方案，在最初3个月内增加了髓样细胞、血小板和总活化MO群体；然而，在此期间ADCC反应并未持续增强。
