Journal Article

PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas

Kurzrock, Razelle, Goodman, Aaron, Patel, Sandip P.

2017

Overview

Key Points A large percentage of patients with classic Hodgkin lymphoma (CHL), primary mediastinal B-cell lymphoma (PMBCL), primary testicular lymphoma, and primary central nervous system lymphoma have copy-number alterations and/or translocations involving the 9p24.1 locus The 9p24.1 locus contains the genes encoding programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2), and JAK2; lymphoma-associated aberrations in this locus result in increased expression of these proteins PD-L1 and/or PD-L2 induce immunosuppressive signalling via programmed cell-death protein 1 (PD-1); blockade of PD-1 with nivolumab results in response rates as high as 87% in patients with relapsed/refractory CHL Nivolumab is currently approved by the FDA for the treatment of relapsed/refractory CHL, and many trials are underway to evaluate PD-1–PD-L1 blockade in patients with B-cell lymphomas The PD-1–PD-L1 axis is probably important for immune evasion of B-cell lymphomas with a viral aetiology, specifically Epstein–Barr virus (EBV)-associated and human immunodeficiency virus (HIV)-associated lymphomas PD-1 inhibition in diffuse large-B-cell lymphoma might be most effective when directed at specific disease subtypes, including PMBCL, T-cell/histiocyte-rich large-B-cell lymphoma, and EBV-positive disease Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed. Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1–PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1–PD-L1 blockade, and the correlations between PD-L1 expression and treatment responses, are less-well elucidated in these diseases than in solid cancers. Nevertheless, in patients with Hodgkin lymphoma, amplification of the gene encoding PD-L1 is commonly associated with increased expression of this protein on Reed–Sternberg cells. Correspondingly, PD-1 blockade with nivolumab has been demonstrated to result in response rates as high as 87% in unselected patients with relapsed and/or refractory Hodgkin lymphoma, leading to the FDA approval of nivolumab for this indication in May 2016. The PD-1/PD-L1 axis is probably also important for immune evasion of B-cell lymphomas with a viral aetiology, including those associated with human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV). This Review is focused on the role of PD-1–PD-L1 blockade in unleashing host antitumour immune responses against various B-cell lymphomas, and summarizes the clinical studies of this approach performed to date.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/699/67/1059/153 / 692/699/67/1059/2325 / 692/699/67/1990/291 / 692/699/67/580 / 692/700/565/251 / Analysis / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Agents - therapeutic use / B cells / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - immunology / B7-H1 Antigen - metabolism / Clinical Trials as Topic / CTLA-4 Antigen - immunology / Drug therapy / Epstein-Barr virus / Health aspects / Hodgkin Disease - drug therapy / Hodgkin Disease - immunology / Human immunodeficiency virus / Humans / Immune response / Immunity, Cellular - immunology / Immunotherapy - methods / Lentivirus / Lymphoma, B-Cell - drug therapy / Lymphoma, B-Cell - immunology / Lymphoma, Follicular - drug therapy / Lymphoma, Follicular - immunology / Lymphomas / Mediastinal Neoplasms - immunology / Mediastinal Neoplasms - therapy / Medicine & Public Health / Oncology / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Programmed Cell Death 1 Receptor - metabolism / Retroviridae / review-article / Risk factors / T cells / Tumor Escape - immunology