Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma

Abstract

Classical Hodgkin lymphoma (cHL) is characterized by nearly universal genetic alterations in 9p24.1, resulting in constitutive expression of PD-1 ligands. This likely underlies the unique sensitivity of cHL to PD-1 blockade, with response rates of ∼70% in relapsed/refractory disease. There are now numerous clinical trials testing PD-1 inhibitors in earlier stages of treatment and in combination with many other therapies. In general, non-Hodgkin lymphomas (NHLs) do not display a high frequency of 9p24.1 alterations and do not share cHL’s vulnerability to PD-1 blockade. However, a few entities have genetic or immunologic features that may predict sensitivity to immune checkpoint blockade. These include primary mediastinal B cell lymphoma, primary central nervous system lymphoma, and primary testicular lymphoma, which harbor frequent alterations in 9p24.1, as well as Epstein Barr virus (EBV)–infected lymphomas, where EBV infection leads to increased PD-L1 expression. Although these subtypes may be specifically vulnerable to PD-1 blockade, the majority of NHLs appear to be minimally sensitive to PD-1 blockade monotherapy. Current investigations in NHL are therefore focusing on targeting other checkpoints or studying PD-1–based combination therapy. Looking forward, additional insight into the most common mechanisms of resistance to immune checkpoint inhibitors will be important to guide rational clinical trial design. In this review, we describe the biological basis for checkpoint blockade in cHL and NHL and summarize the clinical data generated to date. Guided by our rapidly evolving understanding of the pathobiology of various lymphoma subtypes, we are hopeful that the role of checkpoint inhibitors in lymphoma treatment will continue to grow.

EBV microRNA-BHRF1-2-5p targets the 3′UTR of immune checkpoint ligands PD-L1 and PD-L2

“…65 Collectively, this suggests that EBV 1 lymphomas may be specifically vulnerable to strategies that interfere with the PD-1/PD-L1/PD-L2 axis. 66 Therefore, a greater understanding of the molecular basis that underpins the regulation of PD-L1 and PD-L2 expression may identify new therapeutic avenues.…”

High tumoral PD-L1 expression and low PD-1+ or CD8+ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system

“…7,8 PD-1/PD-L1 pathway blockades showed a considerable antitumor effect in patients with many solid tumors and those with refractory or relapsed Hodgkin and non-Hodgkin lymphomas. 9 To date, the PD-1/PD-L1 pathway has been primarily investigated in systemic DLBCL. Several clinicopathological features including Epstein-Barr virus (EBV) infection, 10 chromosome 9p amplification/translocation, 11,12 and activated B-cell-like phenotype were related to increased PD-L1 expression in systemic DLBCL.…”

Primary and acquired resistance mechanisms to immune checkpoint inhibition in Hodgkin lymphoma

“…At the forefront of immune checkpoint therapy are antibodies targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and the programmed cell death-1 (PD-1). However, clinical success of immune checkpoint inhibitors greatly varies between different cancer types, ranging from objective responses in 65-87% of Hodgkin lymphoma (HL) patients to around 30% in other malignancies [reviewed by [1][2][3]].…”