Oligoclonal B cell Expansion and Passenger Fusion Genes Predict Response to Nivolumab in Recurrent Ovarian Cancer: Phase II Kyoto Trial

Background : We previously reported a phase II Kyoto trial for platinum-resistant ovarian cancer (n = 20) using nivolumab (anti-programmed cell death-1 [PD-1] antibody). We evaluated the associations between clinical outcomes and transcriptomics and T and B cell clonality from tumor and blood cells. Methods : We analyzed gene expression microarray with pre- and post-treatment peripheral blood mononuclear cells, α- and β-chain of T cell receptor (TCR) repertoires, and immunoglobulin G (IgG) and M of B cell receptor (BCR) repertoires in 61 samples from 19 patients. Shannon-Weaver diversity scores of the TCR and BCR repertoires were compared between responders and non-responders. RNA sequencing analyzed gene expression and fusion genes in tumor samples (n=17). Results : BCR repertoire analyses of post-/pre-treatment ratios in four responders (two patients with complete response (CR), one with partial response, and one with stable disease near to CR) revealed significantly decreased BCR-IgG repertoires diversity versus non-responders (Shannon-Weaver index, median 0.84 vs. 1.04, p<0.05); the diversity of BCR-IgG repertoires recovered over 100 days. More than two passenger fusion genes were detected in six of the seven responders, whereas eight of the ten non-responders lacked fusion genes. The antitumor response significantly correlated with the number of fusion genes (p=0.0003). Pathway analyses consistently identified immune-related processes, including cytokine-cytokine receptor interactions, neutrophil degranulation, and immunoregulatory interactions in both responders and tumors with high fusion gene counts. Conclusion : Transient oligoclonal expansion of B cells and passenger fusion genes might serve as predictive biomarkers of response to PD-1 blockade in ovarian cancer.