Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy

Abstract

CD19-directed chimeric antigen receptor-modified T cells (CAR T cells) achieve durable remissions in about 30-40% of relapsed/refractory large B-cell lymphomas. T cell exhaustion and/or an immunosuppressive tumor-microenvironment may contribute to CAR T-cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, may reverse T-cell exhaustion following CAR T-cell therapy. We treated 12 patients with B-cell lymphomas who were either refractory to (N=9) or relapsed after (N=3) CD19-directed CAR T cell (4-1BB-costimulated) therapy with pembrolizumab 200mg IV every 3 weeks. Median time from CAR T-cell infusion to first pembrolizumab dose was 3.3 months (range: 0.4-42.8 months). Pembrolizumab was well-tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia (N=3; 25%). Best overall response rate after pembrolizumab was 3/12 (25%) [1 complete response; 2 partial responses]. One (8%) patient had stable disease, thus, 4/12 (33%) patients had clinical benefit. After pembrolizumab, 4 patients with clinical benefit had increase in percentage of CAR T cells by mass cytometry (CyTOF); 3 of 4 of these patients also had increases in CAR19 transgene levels by qPCR. Deep immune profiling using mass cytometry revealed increased CAR T cell activation and proliferation and less T-cell exhaustion in clinical responders. Together, PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy appears safe and may achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy.