Checkpoint Inhibition in Hodgkin Lymphoma: Saving the Best for Last?

Abstract

Hodgkin lymphoma is a unique disease entity characterized by a low number of neoplastic tumor cells surrounded by an inflammatory microenvironment composed of dysfunctional immune cells. Recent molecular and genetic studies have revealed that upregulation of the immune checkpoint pathway programmed death 1/programmed death ligand 1 is a key oncogenic driver of Hodgkin lymphoma. Corroborating these mechanistic studies, early-phase clinical trials using the checkpoint inhibitors nivolumab and pembrolizumab in treatment regimens for relapsed and/or refractory Hodgkin lymphoma have demonstrated impressive response rates, a promising durability of response, and a favorable side-effect profile. Given its targeted mechanism of action, acceptable safety, and clinically meaningful activity, the checkpoint inhibitor nivolumab was recently approved by the US Food and Drug Administration as therapy for classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplantation (ASCT) and post-ASCT consolidation therapy with brentuximab vedotin. In this article we review the scientific rationale, preclinical evidence, and most recent clinical data for the use of checkpoint inhibitor therapy in patients with relapsed Hodgkin lymphoma.

Figure 1.

Mechanisms of upregulating PD-1/PD-L1 pathway in HL. HRS: Hodgkin Reed Sternberg cells TiL: Tumor infiltrating lymphocytes PD1: Program death 1 PDL1: Program death 1 ligand CIITA: CIITA MHCII transcription factor EBV: Epstein Barr virus LMP-1: Latent membrane protein 1