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PD-1阻断型抗体nivolumab在治疗复发或难治性霍奇金淋巴瘤的应用
PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma


Stephen M. Ansell ... 肿瘤 • 2015.01.22
相关阅读
• 霍奇金淋巴瘤的新一线治疗方案

摘要


背景

临床前研究提示Reed-Sternberg(RS)细胞可利用程序化死亡1(programmed death 1,PD-1)信号通路实现免疫逃逸。在经典霍奇金淋巴瘤中,染色体9p24.1区域的改变导致PD-1配体(包括 PD-L1和PD-L2)增多,并且通过Janus激酶(JAK)-转录信号转导和激活物(STAT)信号通路促进其诱导。我们假设PD-1阻断型抗体nivolumab能抑制复发或难治性霍奇金淋巴瘤患者中存在的免疫逃逸。

 

方法

在这项正在进行的临床研究中,23名患有复发或难治性霍奇金淋巴瘤的患者(曾接受过多项治疗而失败),每两周接受一次nivolumab治疗(治疗剂量为3 mg/kg体重),直到肿瘤完全缓解、肿瘤恶化或者出现严重毒性作用。研究的目的是测定治疗的安全性、有效性和评估PDL1PDL2(又分别称为CD274PDCD1LG2)基因位点以及PD-L1 和PD-L2蛋白的表达。

 

结果

在23名参加临床试验的患者中,78%的患者是接受自体干细胞移植后复发的患者,还有78%的患者是接受bretuximab vedotin治疗后复发的患者。78%的患者发生药物相关的副作用,22%患者的不良事件为3级。20名(87%)患者达到客观缓解,其中17%完全缓解,70%部分缓解,余下的3名患者(13%)肿瘤稳定。24周时,疾病无进展生存率为86%,11名患者继续参加此项试验。6名患者因为接受干细胞移植退出试验,4名患者因肿瘤恶化退出,另外2名患者因为药物毒副作用退出。对10名患者治疗前的肿瘤标本分析显示,PDL1PDL2基因拷贝数增多,且其配体蛋白表达增加。Reed-Sternberg细胞核的磷酸化STAT3表达呈阳性,说明细胞内JAK-STAT信号通路处于激活状态。

 

结论

在既往接受过多次治疗的复发或难治性霍奇金淋巴瘤中,nivolumab具有显著的治疗活性以及可接受的安全性(施贵宝公司[Bristol-Myers Squibb]等资助;ClinicalTrials.gov注册号为NCT01592370)。





作者信息

Stephen M. Ansell, M.D., Ph.D., Alexander M. Lesokhin, M.D., Ivan Borrello, M.D., Ahmad Halwani, M.D., Emma C. Scott, M.D., Martin Gutierrez, M.D., Stephen J. Schuster, M.D., Michael M. Millenson, M.D., Deepika Cattry, M.S., Gordon J. Freeman, Ph.D., Scott J. Rodig, M.D., Ph.D., Bjoern Chapuy, M.D., Ph.D., Azra H. Ligon, Ph.D., Lili Zhu, M.S., Joseph F. Grosso, Ph.D., Su Young Kim, M.D., Ph.D., John M. Timmerman, M.D., Margaret A. Shipp, M.D., and Philippe Armand, M.D., Ph.D.
From the Mayo Clinic, Rochester, MN (S.M.A.); Memorial Sloan Kettering Cancer Center (A.M.L., D.C.) and Weill Cornell Medical College (A.M.L.) — both in New York; Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore (I.B.); University of Utah Huntsman Cancer Institute, Salt Lake City (A.H.); Oregon Health and Science University and the Knight Cancer Institute, Portland (E.C.S.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack (M.G.), and Bristol-Myers Squibb, Lawrenceville (L.Z., J.F.G., S.Y.K.) — both in New Jersey; Abramson Cancer Center, University of Pennsylvania (S.J.S.), and Fox Chase Cancer Center (M.M.M.) — both in Philadelphia; Dana–Farber Cancer Institute (G.J.F., B.C., M.A.S., P.A.) Brigham and Women's Hospital (S.J.R., A.H.L.), and Harvard Medical School (G.J.F., B.C., M.A.S., P.A., S.J.R., A.H.L.) — all in Boston; and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles (J.M.T.). Address reprint requests to Dr. Ansell at the Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or atansell.stephen@mayo.edu; or to Dr. Armand at the Dana–Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, or at philippe_armand@dfci.harvard.edu.

 

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