Groenewegen Gerard, Bloem Andries, De Gast Gijsbert C
Department of Oncology, University Medical Centre Utrecht, P.O. Box 85500, 3508GA Utrecht, the Netherlands.
Cancer Immunol Immunother. 2002 Dec;51(11-12):630-6. doi: 10.1007/s00262-002-0323-1. Epub 2002 Oct 15.
A regimen of sequential chemoimmunotherapy (SCIT) was studied in a phase I/II study to analyze toxicity, anti-tumor and immunomodulatory effects in patients with previously untreated metastatic cutaneous melanoma. Treatment consisted of dacarbazine (DTIC) 800 mg/m2 administered intravenously (i.v.) on day 1, followed by subcutaneous (s.c.) molgramostim (GM-CSF), 10 times 2.5 micro g/kg on days 2 to 12, s.c. low-dose interleukin-2 (IL-2), 10 times 1.8 MU on days 8 to 18, and s.c. interferon-alpha-2b (IFN-alpha), 5 times 6 MU on days 15 to 20. Dosages were not escalated. Therapy was given in the form of outpatient treatment. Changes in T-lymphocyte phenotype and in soluble mediators were monitored during treatment. A total of 32 patients with stage IV melanoma were enrolled in the study. Treatment was well tolerated, without serious toxicity. In all cases, it could be given as outpatient treatment. Ten subjects out of the 31 patients evaluated showed an objective response, with 4 complete responses (CR) and 6 partial responses (PR); the response rate amounted to 32% (95% CI: 16-49%). Median survival of all patients was 8 months, with those patients who responded to treatment living longer than the non-responding group. Survival rate at 1 year was 22%. Monitoring of the effects of treatment revealed increased numbers of activated T-lymphocytes, both in the CD4 and in the CD8 subsets. The levels of soluble mediators such as sIL-2R and sCD8 were also increased. Changes were noted as early as the GM-CSF treatment period, and were observed to a further extent during IL-2 treatment. In the present study, it was found that this sequential chemoimmunotherapy regimen consisting of 4 agents (DTIC, GM-CSF, IL-2, IFN-alpha) has acceptable toxicity, can be administered on an outpatient basis, results in increased numbers of activated T-lymphocytes, and induces activity against metastatic melanoma that warrants further investigation.
在一项I/II期研究中，对序贯化学免疫疗法（SCIT）方案进行了研究，以分析其对先前未经治疗的转移性皮肤黑色素瘤患者的毒性、抗肿瘤和免疫调节作用。治疗方案包括：第1天静脉注射（i.v.）达卡巴嗪（DTIC）800mg/m²，随后在第2至12天皮下（s.c.）注射莫拉司亭（GM-CSF），10次，每次2.5μg/kg；在第8至18天皮下注射低剂量白细胞介素-2（IL-2），10次，每次1.8MU；在第15至20天皮下注射干扰素-α-2b（IFN-α），5次，每次6MU。剂量未进行递增。治疗以门诊治疗的形式进行。在治疗期间监测T淋巴细胞表型和可溶性介质的变化。共有32例IV期黑色素瘤患者纳入该研究。治疗耐受性良好，无严重毒性。在所有情况下，均可作为门诊治疗给予。在评估的31例患者中，有10例出现客观缓解，其中4例完全缓解（CR），6例部分缓解（PR）；缓解率为32%（95%CI：16-49%）。所有患者的中位生存期为8个月，对治疗有反应的患者比无反应组存活时间更长。1年生存率为22%。对治疗效果的监测显示，CD4和CD8亚群中活化T淋巴细胞的数量均增加。可溶性介质如sIL-2R和sCD8的水平也升高。早在GM-CSF治疗期间就注意到了变化，在IL-2治疗期间变化更为明显。在本研究中，发现这种由4种药物（DTIC、GM-CSF、IL-2、IFN-α）组成的序贯化学免疫疗法方案具有可接受的毒性，可在门诊进行给药，可导致活化T淋巴细胞数量增加，并诱导针对转移性黑色素瘤的活性，值得进一步研究。
