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Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer
Journal of the National Cancer Institute ( IF 10.3 ) Pub Date : 2017-11-15 , DOI: 10.1093/jnci/djx213
Anshuman Panda 1, 2 , Janice M Mehnert 3, 4, 5 , Kim M Hirshfield 3, 5 , Greg Riedlinger 6, 7 , Sherri Damare 4, 8 , Tracie Saunders 4, 8 , Michael Kane 9 , Levi Sokol 10 , Mark N Stein 3, 4, 5 , Elizabeth Poplin 3, 4, 5 , Lorna Rodriguez-Rodriguez 11, 12 , Ann W Silk 3, 4, 5 , Joseph Aisner 3, 4, 5 , Nancy Chan 3, 4, 5 , Jyoti Malhotra 3, 4, 5 , Melissa Frankel 4, 8 , Howard L Kaufman 4, 13, 14 , Siraj Ali 15 , Jeffrey S Ross 15, 16 , Eileen P White 17, 18 , Gyan Bhanot 1, 2, 18 , Shridar Ganesan 3, 5
Affiliation  

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti–programmed death–ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low–mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.

中文翻译:

埃博拉单抗在EBV阳性胃癌中的免疫激活作用和获益

对免疫检查点治疗的反应可能与高突变负担相关,但其他机制也可能很重要。我们确定了患有转移性胃癌的患者,该患者可通过抗编程死亡配体1(PD-L1)抗体avelumab的治疗获得有意义的临床收益。该肿瘤未显示出高突变负担或错配修复缺陷的证据,但对于爱泼斯坦-巴尔病毒(EBV)编码的RNA的存在呈强阳性。癌症基因组图谱的胃癌数据分析(25 EBV +,80微卫星不稳定[MSI],310微卫星稳定[MSS])显示EBV阳性肿瘤为MSS。双向Wilcoxon秩和检验表明:1)EBV阳性肿瘤的突变负担低(在log 10量表中,中位数= 2.07 vs 3.13 ,P <10-12),但有更强的免疫浸润证据(ImmuneScore 2212 vs 1295,P <10 -4;CD8A的log 2倍变化= 1.85,P <10 -6),与MSI肿瘤相比; 2)EBV阳性肿瘤在RNA-seq数据中具有较高的免疫检查点途径(PD-1,CTLA-4途径)基因表达(对数2倍变化:PD-1 = 1.85,PD-L1 = 1.93,PD-L2 = 1.50,CTLA- 4 = 1.31,CD80 = 0.89,CD86 = 1.31,P分别为P <10 -4)和组织学检查显示较高的淋巴细胞浸润(中位肿瘤浸润淋巴细胞评分= 3 vs 2,P<.001)与MSS肿瘤相比。这些数据表明,EBV阳性的低突变负担型胃癌是MSS胃癌的一个子集,可能对免疫检查点疗法产生反应。
更新日期:2017-11-15
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