Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma
Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma
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DOI：
10.1215/s1522851705000475
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发表时间：
2006-01-01
期刊：
影响因子：
15.9
通讯作者：
Carpentier, AF
中科院分区：
文献类型：
--
作者：
Carpentier, A;Laigle-Donadey, F;Carpentier, AF
含CpG基序的寡脱氧核苷酸（CpG ODN）显示出强烈的免疫刺激活性，并驱动免疫应答朝向Th 1（T辅助细胞1型）表型。这些ODN在临床前研究中局部注射到几种癌症模型中时显示出有希望的疗效。我们进行了一项1期试验，以确定CpG-28（一种硫代磷酸CpG ODN）在复发性胶质母细胞瘤患者中通过对流增强递送瘤内给药的安全性。用递增剂量的CpG-28（0.5-20 mg）治疗三至六名患者的群组，并且观察患者至少四个月。24名患者入组试验。所有患者以前都接受过放疗，大多数患者接受过一种或多种类型的化疗。中位年龄为58岁（范围：25-73岁），中位KPS为80%（范围：60%-100%）。可能或很可能与研究药物相关的不良反应为中度，主要包括神经系统疾病恶化（4例患者）、几天内消失的38 ℃以上发热（5例患者）和可逆性3级淋巴细胞减少症（7例患者）。仅1例患者出现剂量限制性毒性。初步证据表明，活动的轻微反应，观察到两名患者和7.2个月的总中位生存期。总之，在复发性胶质母细胞瘤患者中，每次注射剂量高达20 mg的CpG-28耐受性良好。主要副作用仅限于短暂的神经系统疾病恶化和发热。
Oligodeoxynucleotides containing CpG motifs (CpG ODNs) display a strong immunostimulating activity and drive the immune response toward the Th1 (T helper type 1) phenotype. These ODNs have shown promising efficacy in preclinical studies when injected locally in several cancer models. We conducted a phase 1 trial to define the safety profile of CpG-28, a phosphorothioate CpG ODN, administered intratumorally by convection-enhanced delivery in patients with recurrent glioblastoma. Cohorts of three to six patients were treated with escalating doses of CpG-28 (0.5-20 mg), and patients were observed for at least four months. Twenty-four patients entered the trial. All patients had previously been treated with radiotherapy, and most patients had received one or several types of chemotherapy. Median age was 58 years (range, 25-73) and median KPS was 80% (range, 60%-100%). Adverse effects possibly or probably related to the studied drug were moderate and consisted mainly in worsening of neurological conditions (four patients), fever above 38 degrees C that disappeared within a few days (five patients), and reversible grade 3 lymphopenia (seven patients). Only one patient experienced a dose-limiting toxicity. Preliminary evidence of activity was suggested by a minor response observed in two patients and an overall median survival of 7.2 months. In conclusion, CpG-28 was well tolerated at doses up to 20 mg per injection in patients with recurrent glioblastoma. Main side effects were limited to transient worsening of neurological condition and fever.