O'Mahony Deirdre, Morris John C, Quinn Cate, Gao Wendy, Wilson Wyndham H, Gause Barry, Pittaluga Stefania, Neelapu Sattva, Brown Margaret, Fleisher Thomas A, Gulley James L, Schlom Jeffrey, Nussenblatt Robert, Albert Paul, Davis Thomas A, Lowy Israel, Petrus Mike, Waldmann Thomas A, Janik John E
Metabolism Branch, Laboratory of Pathology, Department of Laboratory Medicine, National Eye Institute, Bethesda, MD 20892-1457, USA.
Clin Cancer Res. 2007 Feb 1;13(3):958-64. doi: 10.1158/1078-0432.CCR-06-1974.
Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.
Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.
Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.
Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
11例在接种癌症疫苗后出现进展性晚期恶性肿瘤的患者接受了全人源抗CTLA-4单克隆抗体（伊匹单抗）治疗。主要终点是确定药物毒性。肿瘤反应、肿瘤特异性CD8+T细胞免疫反应以及CD4+CD25+FoxP3+调节性T细胞（Treg）数量的调节是次要终点。
治疗了3例结肠癌患者、4例非霍奇金淋巴瘤患者和4例前列腺癌患者。首剂剂量为3mg/kg，随后每月给予1.5mg/kg，共4个周期。
2例淋巴瘤患者出现肿瘤消退；其中1例获得了持续14个月的部分缓解。伊匹单抗耐受性良好，主要为1/2级毒性。观察到1例与药物相关的3级毒性。1例患者在治疗后30天内死于进展性结肠癌。治疗后未观察到疫苗特异性T细胞反应增加。通过CD4+CD25+CD62L+表达检测到的Tregs在早期时间点下降，但在下一次输注时反弹至基线值或高于基线值的水平。
在这些先前接受过多种研究性抗癌疫苗治疗的患者中，伊匹单抗治疗在治疗周期的早期时间点降低了Treg数量，但并未伴随着疫苗特异性CD8+T细胞反应的增加。1例滤泡性淋巴瘤患者出现部分缓解。目前正在进行一项评估伊匹单抗治疗滤泡性淋巴瘤患者的I/II期试验。
