PD-1/PD-L1 Pathway and Its Blockade in Patients with Classic Hodgkin Lymphoma and Non-Hodgkin Large-Cell Lymphomas

Purpose of Review: Programmed cell death protein-1 (PD-1) is currently the most extensively studied inhibitory checkpoint molecule. Many malignant neoplasms express the PD-1 ligands, PD-L1, and/or PD-L2, which bind to PD-1 on T cells and induce T cell “exhaustion.” By doing so, the malignant cells escape from an antitumor immune response (immune evasion). Blockade of the PD-1/PD-L1 pathway releases T cells from the inhibitory effects exerted by tumor cells and restores a T cell-mediated antitumor immune response. Here, we focus on understanding the immune biology of the PD-1/PD-L1 pathway in large-cell lymphomas, including classic Hodgkin lymphoma (CHL), diffuse large B cell lymphoma (DLBCL), and anaplastic large-cell lymphoma (ALCL), and the current status of PD-1 blockade immunotherapy in treating patients with these lymphomas. Recent Findings: PD-1/PD-L1 pathway and PD-1 inhibitors have been widely tested in patients with a variety of lymphomas. Nivolumab and pembrolizumab have been approved by the U.S. Food and Drug Administration for treating patients with some types of relapsed or refractory (R/R) lymphomas. The highest response rate has been achieved in patients with CHL, due to a high frequency of genetic alterations of 9p24.1 and high expression of PD-1 ligands. The frequency of alterations of chromosome 9p24.1 and expression of PD-L1/PD-L1 in DLBCL (except some specific subtypes) is low; therefore, it is not recommended to treat unselected DLBCL patients with PD-1 inhibitors. Studies have shown a high frequency of PD-L1 expression in ALCL, especially in anaplastic lymphoma kinase (ALK)+ type. Several cases reports have described a dramatic and durable response to PD-1 blockade in patients with R/R ALCL, suggesting that patients with R/R ALCL may be potential candidates for PD-1 blockade immunotherapy. Summary: Understanding the immune biology of lymphoid neoplasms has helped us identify the specific lymphoma types that are vulnerable to PD-1 inhibitors, such as CHL, and specific subtypes of DLBCL. However, our knowledge of many other lymphomas, including ALCL, in this area is still very limited and the future of PD-1 inhibitors in treating those lymphomas remains unclear.