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

Abstract

Programmed cell death protein 1 (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/programmed death-ligand 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, 9p24.1 genetic alteration, and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORRs) of 65% to 87% and durable disease control in phase 1/2 clinical trials. The median duration of response was 16 months in a phase 2 trial. PD-1 blockade has also shown promise in a phase 1 trial of nivolumab in relapsed/refractory B-cell non-Hodgkin lymphomas, including follicular lymphoma, which often displays abundant PD-1 expression on intratumoral 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 9p24.1 alterations, the ORR was 35% in a phase 2 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 2 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 currently anti-PD-1 clinical trial data are not available. Mechanisms and predictive biomarkers for PD-1 blockade immunotherapy, treatment-related adverse events, hyperprogression, and combination therapies are discussed in the context of B-cell lymphomas.

Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice

“…Standardized incidence ratios of splenic marginal zone lymphomas is markedly increased in young adults after solid organ transplantation (Clarke et al, 2013), a clear indication that immune surveillance may prevent emergence of these lymphomas. Consistently, the presence of PD-1 positive exhausted T-cells has been reported in marginal zone lymphomas (Xu-Monette et al, 2017). All indolent lymphomas may evolve towards aggressive transformation with an increased proliferation index and decreased tumor doubling time.…”

Chronic lymphocytic leukaemia: the role of T cells in a B cell disease

“…So far there has been very limited testing of anti‐PD‐1 or PD‐L1 therapy in CLL. Interim results presented at conferences have not provided any firm conclusions for efficacy to date (Xu‐Monette et al , ). A trial of anti‐PD‐1 (pembrolizumab) therapy in relapsed and Richter‐transformed patients demonstrated objective clinical responses in the Richter‐transformed patients (4/9) but none in the relapsed CLL patients ( n = 16) (Table ; Ding et al , ).…”

Pre-Clinical Blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma

“…Expression of PD-L1 by tumor cells and effect of anti-PD-1 immune therapy has been clearly demonstrated in Hodgkin’s lymphoma, a tumor which is constantly associated with both NF-κB and STAT3 activation. In DLBCL, expression of PD-L1 is variable but participates to the gene immune escape signature of ABC-DLBCLs (3,7). ABC-DLBCL are not only associated with NF-κB activation but may exhibit a chronic active BCR (13) and are sensitive to BTK inhibitors (14).…”

“…Efficacy of immunotherapies against the PD-1/PD-L1 axis in breast or colon cancers demonstrated the importance of the immune checkpoints in the control of emergence and growth of tumors (2). As reviewed recently, various publications have indicated that disruption of immune checkpoints is also a critical step in B-cell non-Hodgkin’s Lymphomas (NHL) (3). NF-κB, one of the most cited transcription factor in B-cell lymphomas, is able to increase tumor cell expression of PD-L1 either directly or indirectly (3).…”