Emerging treatment options for the management of Hodgkin's lymphoma: clinical utility of nivolumab

Abstract

Classical Hodgkin's lymphoma (cHL) is a B-cell malignancy comprised of pathologic Reed Sternberg cells with a surrounding immune-tolerant inflammatory milieu. RS cells evade immune recognition in part through programmed death ligand 1 (PD-L1) overexpression, which is genetically programmed through copy number alterations, polysomy, and amplification of the 9p24.1 locus encoding PD-L1. By engaging with PD-1+ T-cells, PD-L1 delivers a potent immune suppressive signal promoting immunologic escape of the tumor cell. Enhancing antitumor immune response by targeting PD-1 with the monoclonal antibody nivolumab has proved to be effective in multiple solid tumors, but the highest response rates to date have been reported in patients with cHL, with over 65% of treated patients achieving an objective clinical response. In this review, we will summarize the published evidence regarding the activity of nivolumab in cHL as well as its current place in therapy. We will review the pharmacology, mechanism of action, and side effects of nivolumab as well as the emerging data indicating possible increased risk of graft versus host disease in patients treated with PD-1 inhibitors either pre- or post-allogeneic stem cell transplant. Given the remarkable single-agent activity and safety profile of PD-1 inhibitors in heavily pretreated patients with cHL, the possibility of employing nivolumab in combination with other active agents and earlier in therapy is a promising area of active investigation, and we will briefly summarize current clinical trials.

Keywords: Hodgkin’s lymphoma; checkpoint inhibitor therapy; nivolumab; pembrolizumab.

Figure 1

This figure depicts PD-L1 and PD-L2 signaling between an RS cell and a T-cell within the tumor microenvironment. Notes: In addition to acting as a ligand for PD-1 leading to inhibitory signaling through suppression of SHP-2, PD-L1 also acts as a receptor for CD 80 on antigen presenting cells, thereby inhibiting binding of CD 80 with CD 28 on T cells. PD-1 inhibitors bind PD-1, thus attenuating PD-1 mediated T-cell exhaustion. Abbreviations: PD-1, programmed death 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; RS, Reed Sternberg cell; SHP-2, Src homology phosphotase 2.