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Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer

2017; Oxford University Press; Volume: 110; Issue: 3 Linguagem: Inglês

10.1093/jnci/djx213

1460-2105

Anshuman Panda, Janice M. Mehnert, Kim M. Hirshfield, Gregory Riedlinger, Sherri Damare, Tracie Saunders, Michael P. Kane, Levi Sokol, Mark N. Stein, Elizabeth Poplin, Lorna Rodríguez-Rodríguez, Ann W. Silk, Joseph Aisner, Nancy Chan, Jyoti Malhotra, Melissa Frankel, Howard L. Kaufman, Siraj M. Ali, Jeffrey S. Ross, Eileen White, Gyan Bhanot, Shridar Ganesan,

Lymphoma Diagnosis and Treatment

Abstract 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.