Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial
Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial
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DOI：
10.1007/s00262-012-1242-4
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发表时间：
2012-10-01
影响因子：
5.8
通讯作者：
Svane, Inge Marie
中科院分区：
文献类型：
--
作者：
Ellebaek, Eva;Engell-Noerregaard, Lotte;Svane, Inge Marie
树突状细胞（DC）是最有效的抗原提呈细胞，并已被证明在体内刺激特异性免疫应答中是有效的。竞争性免疫抑制可能限制DC疫苗接种的临床疗效。在该II期试验中，将节拍环磷酰胺和考克斯-2抑制剂添加到DC疫苗中，旨在抑制免疫抑制机制。28例进行性转移性黑色素瘤患者接受了用生存素、hTERT和p53衍生肽（HLA-A2（+））或肿瘤裂解物（HLA-A2（-））脉冲的自体DC治疗。患者同时接受IL-2、环磷酰胺和塞来昔布治疗。治疗是安全和可耐受的。16例患者（57%）在首次评价时达到疾病稳定（SD），8例患者SD延长（7-13.7个月）。中位OS为9.4个月。SD患者的OS为10.5个月，而疾病进展（PD）患者的OS为6.0个月（p = 0.048），尽管两组之间的预后因素无差异。尽管使用节拍环磷酰胺，调节性T细胞在治疗期间没有减少。间接IFN-γ ELISPOT试验显示，从基线到第4次接种时，免疫应答普遍增加。15例HLA-A2（+）患者中有9例出现抗原特异性免疫应答。总之，与先前未使用环磷酰胺和塞来昔布的试验相比，获得SD的患者数量增加了一倍以上，6个月生存期显著增加。观察到针对测试肽的免疫应答普遍增加。
Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2(+)) or tumor lysate (HLA-A2(-)). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7-13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-gamma ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2(+) patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed.