Pd‐1 and lag‐3 checkpoint blockade: Potential avenues for therapy in b‐cell lymphoma

Abstract

The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor‐induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD‐1 mediated immune suppression in a range of cancers. However, while PD‐1 blockade has been paradigm‐shifting in many malignancies, the majority of cancers show high rates of primary resistance to this approach. This has led to a rapid expansion in therapeutic targeting of other immune checkpoint molecules to provide combination immune checkpoint blockade (ICB), with one such promising approach is blockade of Lymphocyte Activation Gene 3 (LAG‐3). Clinically, lymphoproliferative disorders show a wide spectrum of responses to ICB. Specific subtypes including classical Hodgkin lymphoma have demonstrated striking efficacy with anti‐PD‐1 therapy. Conversely, early trials of ICB have been relatively disappointing in common subtypes of Non‐Hodgkin lymphoma. In this review, we describe the TME of common lymphoma subtypes with an emphasis on the role of prominent immune checkpoint molecules PD‐1 and LAG3. We will also discuss current clinical evidence for ICB in lymphoma and highlight key areas for further investigation where synergistic dual checkpoint blockade of LAG‐3 and PD‐1 could be used to overcome ICB resistance.