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PD-1 expression and clinical PD-1 blockade in B-cell lymphomas

Zijun Y. Xu-Monette, Jianfeng Zhou and Ken H. Young

Abstract

PD-1 blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/PD-L1 expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD-1+ tumor-infiltrating T cells, 9p24 genetic alteration and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORR) of 65-87% and durable disease control in phase I/II clinical trials. The median duration of response was 16 months in a phase II trial. PD-1 blockade has also shown promise in a phase I trial of nivolumab in relapsed/refractory B-cell non-Hodgkin lymphomas, including follicular lymphoma, which often displays abundant PD-1 expression on intratumoral CD4+ T cells, and diffuse large B-cell lymphoma, which variably expresses PD-1 and PD-L1. In primary mediastinal large B-cell lymphoma, which frequently has 9p24 alterations, the ORR was 35% in a phase II trial of pembrolizumab. In contrast, the ORR with pembrolizumab was 0% in relapsed chronic lymphocytic leukemia (CLL) and 44% in CLL with Richter transformation in a phase II trial. T cells from CLL patients have elevated PD-1 expression; CLL PD-1+ T cells can exhibit a pseudo-exhaustion or a replicative senescence phenotype. PD-1 expression was also found in marginal zone lymphoma but not in mantle cell lymphoma, although no reliable PD-1 blockade data are currently available. Mechanisms of PD-1 blockade immunotherapy, toxicities, hyperprogression, predictive biomarkers and combination therapies are discussed in the context of B-cell lymphomas.

  • Submitted July 5, 2017.
  • Accepted October 28, 2017.