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

Anshuman Panda(Rutgers, The State University of New Jersey), Janice M. Mehnert(Rutgers, The State University of New Jersey), Kim M. Hirshfield(Rutgers, The State University of New Jersey), Gregory Riedlinger(Rutgers, The State University of New Jersey), Sherri Damare(Rutgers, The State University of New Jersey), Tracie Saunders(Rutgers, The State University of New Jersey), Michael P. Kane(Rutgers, The State University of New Jersey), Levi Sokol(Rutgers, The State University of New Jersey), Mark N. Stein(Rutgers, The State University of New Jersey), Elizabeth Poplin(Rutgers, The State University of New Jersey), Lorna Rodríguez-Rodríguez(Rutgers, The State University of New Jersey), Ann W. Silk(Rutgers, The State University of New Jersey), Joseph Aisner(Rutgers, The State University of New Jersey), Nancy Chan(Rutgers, The State University of New Jersey), Jyoti Malhotra(Rutgers, The State University of New Jersey), Melissa Frankel(Rutgers, The State University of New Jersey), Howard L. Kaufman(Rutgers, The State University of New Jersey), Siraj M. Ali(Foundation Medicine (United States)), Jeffrey S. Ross(Foundation Medicine (United States)), Eileen White(Rutgers, The State University of New Jersey), Gyan Bhanot(Rutgers, The State University of New Jersey), Shridar Ganesan(Rutgers, The State University of New Jersey)
JNCI Journal of the National Cancer Institute
October 6, 2017
10.1093/jnci/djx213
Cited by 214Open Access
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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.

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