Clinical PD-1/PD-L1 Blockades in Combination Therapies for Lymphomas

SIMPLE SUMMARY: Immunotherapy using antibodies against programmed cell death protein 1 (PD-1) or its ligand PD-L1 can restore host antitumor immunity in many types of cancer. Hence, PD-1/PD-L1 blockade therapy has become the standard treatment for various cancer types in the last decade. However, apart from classic Hodgkin lymphoma and primary mediastinal B-cell lymphoma, PD-1/PD-L1 blockade therapy has shown limited efficacy in other lymphomas. To address this gap, several clinical trials of combination therapies with PD-1/PD-L1 inhibitors have been recently conducted or are underway in both frontline and relapsed/refractory settings. Here, we comprehensively review these clinical studies of combination therapies for lymphomas and discuss their outcomes in the hope of providing a perspective to develop novel therapeutic approaches for combination therapy. ABSTRACT: Immunotherapy with the programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) blockade has revolutionized the treatment of advanced solid cancers. However, these clinical benefits have been limited to cases of malignant lymphomas, showing promising results for only classic Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL). To bring clinical benefits to more patients with lymphoma, numerous combination therapies involving PD-1/PD-L1 blockade have been tested in clinical trials in both frontline and relapsed/refractory settings. This article reviews the current landscape of combination therapies with PD-1/PD-L1 blockade for lymphoma and discusses the potential therapeutic approaches. An interim analysis of a phase 3 study demonstrated increased progression-free survival with nivolumab combination therapy over the current frontline treatment in patients with advanced-stage cHL. The results of combination therapies for aggressive B-cell lymphomas, except for PMBCL, have been disappointing. Several clinical trials of combined PD-1/PD-L1 blockade and Bruton’s tyrosine kinase inhibitors are exploring its efficacy in patients with chronic lymphocytic leukemia (CLL) with Richter transformation. Several T-cell lymphoma subtypes respond to PD-1/PD-L1 blockade monotherapy. Further clinical trials are underway to investigate appropriate combination regimens with PD-1/PD-L1 blockade, especially for cHL, CLL with Richter transformation, and T-cell lymphoma, in both frontline and relapsed/refractory settings.