George Davatelis, PhD — Contributing Author
Hodgkin lymphoma (HL) is a cancer of the immune system that is marked by the presence of a type of cell called the Reed-Sternberg cell. The 2 major types of HL are classical HL and nodular lymphocyte–predominant HL.1 In 2014, there were more than 9000 new patients diagnosed with HL and more than 1000 deaths.2 HL is more common among young adults than older adults and more common among men than women.2 The treatment of patients with HL is one of the major success stories in oncology, and 60% to 90% of patients are cured of their malignancy depending on clinical stage and risk factors.3 However, whereas current therapies have been highly successful in treating the disease, approximately one-quarter of patients eventually suffer a relapse.
Fortunately for these patients, researchers are investigating a new class of immunotherapy (also called immuno-oncology) products that shows promising results in treating patients with many types of tumors, including relapsed or refractory HL. It has been known for many years that cancer cells protect themselves from an immune system attack by turning off immune responses or otherwise camouflaging themselves. Immunotherapy works directly with a patient’s immune system to re-engage the immune system to attack the tumor cells directly. Agents that help the immune system identify and attack cancer cells have the potential to be very effective therapies for a plethora of neoplasms.
Normally, immune checkpoint pathways—a series of innate inhibitory pathways in the immune system—prevent excessive effector activity by T cells and prevent the immune system from overreacting to stimuli or prevent it from misidentifying the patient’s own healthy cells as a harmful invader.4 The PD-1 (program cell death 1) pathway functions as an immune checkpoint that temporarily moderates immune responses to chronic antigen stimulation. However, tumor cells can stimulate abnormal expression of PD-1 and its ligands, PD-L1 and PD-L2, and co-opt the checkpoint pathway to evade detection by T cells4 as well as induce T-cell exhaustion, a reversible inhibition of T-cell activation and proliferation.5
This may have particular significance in treating HL, in which preclinical studies suggest that Reed-Sternberg cells exploit the PD-1 pathway to evade immune detection. In classic HL, chromosome 9p24.1 gain is a fairly common mutation that is linked to elevated expression of the PD-1 ligands, PD-L1 and PD-L2, and their induction via Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Epstein-Barr virus (EBV) infection also increases the expression of the PD-1 ligands in EBV-positive classic HL, and ligand binding to PD-1 receptor–positive activated T cells then induces T-cell exhaustion.6
Positive Results in Clinical Trials for PD-1 Inhibitors in Patients With HL
Nivolumab (BMS-936558; Bristol-Myers Squibb) is a fully human IgG4 monoclonal PD-1 blocking antibody that potentiates antitumor T-cell activity and exhibits clinical efficacy in several solid tumors. Preliminary safety, efficacy, and biomarker results of a phase 1 study in patients with relapsed or refractory HL was recently reported at the American Society of Hematology (ASH) 2014 Annual Meeting and Exposition.6 In this ongoing study, 23 patients with relapsed or refractory HL that had already been heavily treated received nivolumab every 2 weeks until they had a complete response (CR), tumor progression, or excessive toxic effects.
Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation (ASCT) and 78% after a relapse following the receipt of brentuximab vedotin. An objective response was reported in 20 patients (87%), including 17% with a CR and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%, and 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PD-L1 and PD-L2 as well as increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.
The authors of the study concluded that nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory HL. And according to the principal investigator of the study, Philippe Armand, MD, PhD, medical oncologist at Dana-Farber Cancer Institute, “Despite the current treatment landscape, this patient population is still experiencing relatively short-lived responses that often result in relapse. So, there is a critical need to identify new options that can improve outcomes during the course of their care. These findings with Opdivo (nivolumab) are incredibly encouraging because they show that an immuno-oncology approach with a checkpoint blockade has the potential to be applied to lymphomas.”7
Preliminary results of another clinical trial presented at ASH 2014 for another PD-1 checkpoint inhibitor, pembrolizumab (MK-3475; Merck), were also released. Preliminary data from the ongoing, multicenter, open-label, phase 1b clinical trial, KEYNOTE-013,8 were reported for the 15 patients with relapsed or refractory classic HL who were evaluable for response to pembrolizumab at the 12-week time point. The median number of prior therapies was 4, and, by design, all patients previously failed brentuximab vedotin; 67% also failed prior ASCT.8 Pembrolizumab was well tolerated.8 There were no serious adverse events (AEs), and only 1 patient experienced grades 3-5 AEs.8 Based on investigator assessment, 3 patients (20%) had CR at 12 weeks.8 Five additional patients (33%) had partial remission as best overall response, for an overall response rate of 53%.8 Four patients (27%) experienced disease progression, although all 4 experienced a decrease in their overall tumor burden.8
The authors of the study concluded that pembrolizumab therapy appears to be safe, tolerable, and associated with clinical benefit in patients with heavily pretreated classical HL. The principal investigator, Dr Craig Moskowitz, clinical director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, noted that, “These early data presented at ASH 2014 are very promising and show response rates of 66% with pembrolizumab in patients with classical Hodgkin lymphoma. There are few options for patients with multiple relapsed or refractory, classical Hodgkin lymphoma, and pembrolizumab should continue to be studied for the treatment of this cancer.”9
Why Do PD-1 Inhibitors Demonstrate Such Promising Results in HL?
Margaret Shipp, MD, chief, Division of Hematologic Neoplasia at Dana-Farber Cancer Institute and a coauthor of the nivolumab study, offered 2 possible explanations for the high response rate in HL patients: “Hodgkin lymphoma is unusual among cancers in that it consists of a small number of tumor cells in a sea of inflammatory cells and immune system cells, including T cells that don’t work very effectively. Activating those T cells may create a very strong response to a relatively small number of cancer cells. Another related possibility is the genetic trait that causes HL cells to produce an abundance of PD-L1 and PD-L2 ligands makes the tumor particularly vulnerable to PD-1 blockade.”10
1National Cancer Institute. Lymphoma. http://www.cancer.gov/cancertopics/types/hodgkin. Accessed March 18, 2015.
2SEER Stat Fact Sheets: Hodgkin Lymphoma. http://seer.cancer.gov/statfacts/html/hodg.html. Accessed March 18, 2015.
3Illidge T. XVII. Radiotherapy in early stage Hodgkin lymphoma. Hematol Oncol. 2013;31(suppl 1):92-95.
4Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21(1):80-89.
5Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12(6):492-499.
6Armand P, Ansell SM, Lesokhin AM, et al. Nivolumab in patients with relapsed or refractory Hodgkin lymphoma—preliminary safety, efficacy and biomarker results of a phase I study. Presented at 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 289. https://ash.confex.com/ash/2014/webprogram/Paper73050.html. Accessed March 18, 2015.
7Bristol-Myers Squibb. Opdivo (nivolumab) demonstrates high overall response rate of 87% for treatment of relapsed or refractory Hodgkin lymphoma. http://news.bms.com/press-release/opdivo-nivolumab-demonstrates-high-overall-response-rate-87-treatment-relapsed-or-refr. Accessed March 18, 2015.
8Moskowitz CH, et al. PD-1 Blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). Presented at 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 290.https://ash.confex.com/ash/2014/webprogram/Paper75615.html. Accessed March 18, 2015.
9PR Newswire. Merck announces positive data investigating the use of pembrolizumab in patients with classical Hodgkin lymphoma at ASH Annual Meeting.http://www.prnewswire.com/news-releases/merck-announces-positive-data-investigating-the-use-of-pembrolizumab-in-patients-with-classical-hodgkin-lymphoma-at-ash-annual-meeting-284972421.html. Accessed March 18, 2015.
10Dana-Farber Cancer Institute. Immunotherapy achieves breakthrough result in patients with Hodgkin lymphoma. http://www.dana-farber.org/Newsroom/News-Releases/immunotherapy-achieves-breakthrough-result-in-patients-with-hodgkin-lymphoma.aspx. Accessed March 18, 2015.