MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
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DOI：
10.1038/nature13904
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发表时间：
2014-11-27
期刊：
影响因子：
64.8
通讯作者：
Vogelzang, Nicholas J.
中科院分区：
文献类型：
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作者：
Powles, Thomas;Eder, Joseph Paul;Vogelzang, Nicholas J.
在过去的30年中，转移性尿路上皮膀胱癌（UBC）的治疗没有重大进展。化疗仍然是标准治疗。患者结局，尤其是化疗无效或耐受性差的患者，仍然很差（1，2）。UBC的一个标志是存在高比例的体细胞突变（3，5）。由于抗原数量增加，这些改变可能增强宿主免疫系统将肿瘤细胞识别为外来细胞的能力（6）。然而，这些癌症也可能通过肿瘤微环境中程序性死亡配体1（PD-Li;也称为CD 274或B7-H1）的表达逃避免疫监视和根除（7，8）。因此，我们检查了抗PDLi抗体MPDL 3280 A，一种全身性癌症免疫疗法，用于治疗转移性UBC。MPDL 3280 A是一种高亲和力工程化人抗PD-L1单克隆免疫球蛋白-G1抗体，可抑制PD-L1与PD-1（PDCD 1）和B7.1（CD 80）9的相互作用。由于PD-L1在活化的T细胞上表达，因此MPDL 3280 A在Fc结构域中进行了修饰，以消除临床相关剂量下的抗体依赖性细胞毒性，以防止表达PD-Li的T细胞耗竭。在这里，我们显示MPDL 3280 A在转移性UBC中具有值得注意的活性。缓解通常很快，许多发生在首次缓解评估时（6周），几乎所有缓解在数据截止日期时仍在进行中。这项I期扩展研究采用了允许生物标志物阳性富集队列的适应性设计，证明了表达PD-L1阳性肿瘤浸润免疫细胞的肿瘤具有特别高的缓解率。此外，由于有利的毒性特征，包括缺乏肾毒性，患有UBC的患者，通常年龄较大并且具有较高的肾损害发生率，可能比化疗更能耐受MPDL 3280 A。这些结果表明，MPDL 3280 A可能在治疗UBC中发挥重要作用-该药物于2014年6月获得美国食品和药物管理局（FDA）的突破性指定状态。
There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor(1,2). One hallmark of UBC is the presence of high rates of somatic mutations(3,5). These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens(6). However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-Li; also called CD274 or B7-H1) in the tumour microenvironment(7,8). Therefore, we examined the anti-PDLi antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-Gl antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80)9. Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-Li. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1 -positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.