Vaughan M M, Moore J, Riches P G, Johnston S R, A'Hern R P, Hill M E, Eisen T, Ayliffe M J, Thomas J M, Gore M E
Melanoma Unit, Royal Marsden NHS Trust, London, UK.
Ann Oncol. 2000 Sep;11(9):1183-9. doi: 10.1023/a:1008348005349.
Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy.
Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days.
Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha.
The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.
肿瘤抗原处理无效被认为是黑色素瘤免疫治疗失败的一个重要原因。粒细胞-巨噬细胞集落刺激因子（GM-CSF）可通过激活抗原呈递细胞增强细胞毒性淋巴细胞反应。本研究评估了GM-CSF与生物化疗联合的方案。
19例晚期恶性黑色素瘤患者接受顺铂（25mg/m²，第1 - 3天）、达卡巴嗪（220mg/m²，第1 - 3天）、白细胞介素-2（9MIU/m²/24小时）以及干扰素-α2b（5MIU/m²），第6 - 10天和第17 - 21天均使用，同时持续给予他莫昔芬40mg/天。皮下注射GM-CSF，剂量递增，分为三个队列：1）450μg/m²，第4 - 5天和第15 - 16天；2）同1），加用225μg/m²，第6 - 10天和第17 - 21天；3）450μg/m²，第4 - 10天和第15 - 21天。每个周期为28天。
全身性副作用是主要的非血液学毒性，淋巴细胞减少是主要的血液学毒性。6例患者有反应（32%，95%置信区间：13% - 57%），2例患者完全缓解。随着GM-CSF剂量增加，反应有明显增加趋势；队列1的6例反应中0例，队列2的7例中2例，队列3的6例中3例（P = 0.016）。中位总生存期为6.2个月。GM-CSF剂量增加显著提高了新蝶呤和肿瘤坏死因子-α的血清浓度。
GM-CSF与生物化疗联合是可行的，就宿主免疫反应以及可能的临床疗效而言，GM-CSF似乎存在剂量反应关系。
