Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.
N Engl J Med. 2012 Jun 28;366(26):2455-65. doi: 10.1056/NEJMoa1200694. Epub 2012 Jun 2.
Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.
In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.
As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up.
Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).
程序性死亡受体 1（PD-1）蛋白是一种 T 细胞共抑制受体，其配体之一 PD-L1 在肿瘤细胞逃避宿主免疫系统的能力中发挥着关键作用。阻断 PD-1 与 PD-L1 之间的相互作用可增强体外免疫功能，并介导临床前模型中的抗肿瘤活性。
在这项多中心的 1 期临床试验中，我们给选定的晚期癌症患者静脉注射抗 PD-L1 抗体（剂量从 0.3 毫克/千克至 10 毫克/千克体重递增）。每 14 天给药一次，6 周为一个周期，最多给药 16 个周期，或直至患者完全缓解或确认疾病进展。
截至 2012 年 2 月 24 日，共有 207 例患者（75 例非小细胞肺癌，55 例黑色素瘤，18 例结直肠癌，17 例肾癌，17 例卵巢癌，14 例胰腺癌，7 例胃癌和 4 例乳腺癌）接受了抗 PD-L1 抗体治疗。治疗的中位持续时间为 12 周（范围 2 至 111 周）。研究者认为与治疗相关的 3 级或 4 级毒性作用发生在 9%的患者中。在可评估反应的患者中，观察到黑色素瘤患者中有 9 例（9/52）、肾癌患者中有 2 例（2/17）、非小细胞肺癌患者中有 5 例（5/49）和卵巢癌患者中有 1 例（1/17）出现客观反应（完全或部分缓解）。在至少随访 1 年的 16 例患者中，有 8 例的反应持续了 1 年以上。
抗体介导的 PD-L1 阻断诱导晚期癌症患者（包括非小细胞肺癌、黑色素瘤和肾癌）的肿瘤持久消退（客观缓解率为 6%至 17%）和疾病稳定延长（24 周时的缓解率为 12%至 41%）。（由 Bristol-Myers Squibb 等资助；ClinicalTrials.gov 编号，NCT00729664）。
