Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma.
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma.
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DOI：
10.1158/1078-0432.ccr-15-2839
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发表时间：
2016-11-15
期刊：
影响因子：
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通讯作者：
Sznol M
中科院分区：
文献类型：
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作者：
Choueiri TK;Fishman MN;Escudier B;McDermott DF;Drake CG;Kluger H;Stadler WM;Perez-Gracia JL;McNeel DG;Curti B;Harrison MR;Plimack ER;Appleman L;Fong L;Albiges L;Cohen L;Young TC;Chasalow SD;Ross-Macdonald P;Srivastava S;Jure-Kunkel M;Kurland JF;Simon JS;Sznol M
Nivolumab是一种抗PD-1免疫检查点抑制剂，在先前治疗的转移性肾细胞癌(MRCC)患者的3期试验中，与伊波利马相比，它提高了总存活率。我们在一项假设生成的前瞻性mRCC试验中研究了nivolumab的免疫调节活性。尼伏鲁单抗每3周静脉注射一次，剂量分别为0.3、2或10 mg/kg，用于既往治疗的肾细胞癌患者，以及10 mg/kg治疗初治的mRCC患者。获得基线和治疗中的活组织检查和血样。评估临床活动、肿瘤相关淋巴细胞、PD-L1表达(DAKO免疫组织化学；≥5%与5%肿瘤膜染色)、肿瘤基因表达(AffymetrixU219)、血清趋化因子和安全性。在91例接受治疗的患者中，尼伏单抗0.3 mg/kg组、2 mg/kg组、10 mg/kg组和未治疗初治组的中位总生存期(95%CI)分别为16.4个月(10.1-未达[NR])、2 mg/kg(NR)、25.2个月(12.0-NR)。肿瘤相关淋巴细胞较基线变化的中位数百分比分别为69%(CD3+)、180%(CD4+)和117%(CD8+)。在56例基线活检中，32%有≥5%的PD-L1表达，从基线到治疗中的活检没有一致的变化。治疗后肿瘤的转录变化包括干扰素-γ刺激的基因上调(例如，CXCL9)。从基线到C2D8，外周血中趋化因子水平的中位数分别增加了101%(CXCL9)和37%(CXCL10)。没有发现新的安全信号。通过不同剂量的nivolumab的多条证据证明了PD-1抑制的免疫调节作用。生物标记物的变化反映了尼伏路单抗在肿瘤微环境中的药效学。这些数据可能会为潜在的组合提供信息。
Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. In 91 treated patients, median overall survival (95% CI) was 16.4 months (10.1–not reached [NR]) for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0–NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included up-regulation of interferon-γ–stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations.