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抗PD-1抗体在癌症治疗中的安全性、有效性和免疫的相关性
Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer


Suzanne L. Topalian ... 肿瘤 • 2012.06.28
相关阅读
• Cemiplimab阻断PD-1治疗晚期皮肤鳞状细胞癌 • 纳武利尤单抗联合伊匹单抗与舒尼替尼治疗晚期肾细胞癌的比较研究 • 晚期非小细胞肺癌放化疗后的巩固性免疫疗法 • 纳武利尤单抗一线治疗Ⅳ期或复发性非小细胞肺癌

摘要


背景

阻断由T细胞表达的一种抑制性受体——程序性死亡分子1(PD-1)可以克服免疫抵抗。BMS-936558是一种特异性阻断PD-1的抗体,本研究将评估其在抗肿瘤治疗中的有效性和安全性。

 

方法

研究纳入了晚期黑色素瘤、非小细胞肺癌、去势抵抗性前列腺癌、肾细胞癌和结直肠癌的患者,每2周给予1次抗PD-1抗体治疗,剂量为0.1~10 mg/kg体重,在每1个治疗周期(8周)后评估其疗效。患者接受最多至12个周期的治疗,直到出现了疾病进展或完全缓解。

 

结果

截止至2012年2月24日共有296名患者入组接受了治疗。其中14%的患者出现了3级或4级药物相关不良事件,3名患者死于肺毒性。本研究未确定药物最大耐受剂量。我们观测到免疫相关的药物不良事件。在可评估疗效的236名患者中,在非小细胞肺癌、黑色素瘤或肾细胞癌患者中观察到了客观疗效(完全缓解或部分缓解)。所有剂量下的累计缓解率在非小细胞肺癌患者中为18%(14/76),在黑色素瘤患者中为28%(26/94),在肾细胞癌患者中为27%(9/33)。这些缓解是可持续的,通过1年或以上的随访发现,31名患者中有20名的治疗效果持续了至少1年。为进一步评估肿瘤内PD-L1的表达在调节PD-1–PD-L1通路中的作用,本研究对42位患者治疗前的肿瘤样本进行了免疫组化分析:在17位PD-L1表达阴性的患者中,均未观察到客观疗效;而在25位PD-L1表达阳性的患者中,9位(36%)出现了客观疗效(P=0.006)。

 

结论

在入组的1/5~1/4的非小细胞肺癌、黑色素瘤或肾细胞癌患者中,抗PD-1抗体治疗产生了客观疗效。不良事件发生谱似乎并不足以阻止抗PD-1抗体的使用。初步数据显示PD-L1在肿瘤细胞中的表达和其客观疗效之间存在一定相关性(由百时美施贵宝[Bristol-Myers Squibb]等资助;ClinicalTrials.gov注册号为NCT00730639)。





作者信息

Suzanne L. Topalian, M.D., F. Stephen Hodi, M.D., Julie R. Brahmer, M.D., Scott N. Gettinger, M.D., David C. Smith, M.D., David F. McDermott, M.D., John D. Powderly, M.D., Richard D. Carvajal, M.D., Jeffrey A. Sosman, M.D., Michael B. Atkins, M.D., Philip D. Leming, M.D., David R. Spigel, M.D., Scott J. Antonia, M.D., Ph.D., Leora Horn, M.D., Charles G. Drake, M.D., Ph.D., Drew M. Pardoll, M.D., Ph.D., Lieping Chen, M.D., Ph.D., William H. Sharfman, M.D., Robert A. Anders, M.D., Ph.D., Janis M. Taube, M.D., Tracee L. McMiller, M.S., Haiying Xu, B.A., Alan J. Korman, Ph.D., Maria Jure-Kunkel, Ph.D., Shruti Agrawal, Ph.D., Daniel McDonald, M.B.A., Georgia D. Kollia, Ph.D., Ashok Gupta, M.D., Ph.D., Jon M. Wigginton, M.D., and Mario Sznol, M.D.
From the Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore (S.L.T., J.R.B., C.G.D., D.M.P., W.H.S., R.A.A., J.M.T., T.L.M., H.X.); Dana–Farber Cancer Institute (F.S.H.) and Beth Israel Deaconess Medical Center (D.F.M., M.B.A.) — both in Boston; Yale University School of Medicine and Yale Cancer Center, New Haven, CT (S.N.G., L.C., M.S.); University of Michigan, Ann Arbor (D.C.S.); Carolina BioOncology Institute, Huntersville, NC (J.D.P.); Memorial Sloan-Kettering Cancer Center, New York (R.D.C.); Vanderbilt University Medical Center (J.A.S., L.H.) and Sarah Cannon Research Institute/Tennessee Oncology (D.R.S.) — both in Nashville; Cincinnati Hematology-Oncology, Cincinnati (P.D.L.); H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (S.J.A.); Bristol-Myers Squibb, Milpitas, CA (A.J.K.); and Bristol-Myers Squibb, Princeton, NJ (M.J.-K., S.A., D.M., G.D.K., A.G., J.M.W.). Address reprint requests to Dr. Topalian at the Department of Surgery, Johns Hopkins University School of Medicine, 1550 Orleans St., CRB 2, Rm. 508, Baltimore, MD 21287, or at stopali1@jhmi.edu.

 

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