Transcript:Ian W. Flinn, MD: Hello, and thank you for joining us today for this OncLive Peer Exchange panel discussion on the use of immunotherapy in advanced lymphoid malignancies. Since the approval of rituximab in 1997, we’ve known the success of using immunotherapy to treat lymphoid malignancies. As evidenced by adoptive immunotherapy realized through graft-versus-tumor response following allogeneic stem cell transplantation, which has curative potential for nearly all hematologic malignancies, we know this area offers particularly fertile ground for immune-targeted strategies. Now, with several novel strategies emerging that harness the ability of T lymphocytes to target cancer cells, it’s imperative that hematologists and oncologists understand how these new therapies work and how to use them. In this OncLive Peer Exchange, I’ll be joined by a panel of experts to discuss how the newest immunotherapies will be integrated into modern care of patients with advanced lymphoid malignancies.

I am Dr. Ian Flinn. I’m the director of the Sarah Cannon Center for Blood Cancer in Nashville, Tennessee. Joining me today are Dr. Krishna Komanduri, professor of medicine and director of the Adult Stem Cell Transplant Program at the Sylvester Comprehensive Cancer Center at the University of Miami; Dr. Andre Goy, the chairman and executive director at the John Theurer Cancer Center located in Hackensack, New Jersey; and Dr. Frederick Locke, assistant member and director of the Immune Cellular Therapy and Research Program at the Moffitt Cancer Center in Tampa, Florida.

We know there’s been tremendous success of the checkpoint inhibitors in the treatment of solid tumors. It seems that in the hematologic malignancies, we’re a little bit behind there, but there is some data that’s been emerging about the use of these drugs in that arena. Andre, what’s going on there?

Andre Goy, MD, MS: You’re right. We have heard a lot over the last few years, and at this ASCO in particular, on immunotherapy and checkpoint inhibitors—remarkably, across a number of solid tumors. But we also have cited some work and seen some data in hematological malignancies. More than 2 years ago, we had the first data for checkpoint inhibitors on nivolumab across the board in hematologic cancers in a phase I study, showing activity of about 30% to 40% in a number of different subtypes of non-Hodgkin lymphoma. At about the same time, there was a study on Hodgkin lymphoma in patients who were heavily pretreated, where most had received prior high-dose therapy and transplant. And three-quarters of them had received prior brentuximab. The response rate with nivolumab, which is given at 3 mg/kg every 2 weeks, was actually very impressive at 85% and with almost a 20% complete remission (CR) rate. These response rates we actually updated recently and are very durable, some of them lasting up to 2 years.

At the same time, there is, as you mentioned, a number of other checkpoint inhibitors. So, we have a pembrolizumab study in patients who have relapsed/refractory Hodgkin lymphoma and who, by definition, had to have failed prior brentuximab. Similarly, the response rate was that 50% to 60% attained CR and was very durable. In all of these studies, we see the toxicity profile that we see with checkpoint inhibitors in solid tumors, with a lot of inflammatory autoimmune-type reactions that are usually manageable. And what’s really exciting, it offers us a new platform to develop more in hematologic malignancies in a number of combinations that are actually ongoing.

Ian W. Flinn, MD: Great. Krishna, these are malignancies of the immune system. They’re malignant lymphocytes, yet there’s also normal lymphocytes sometimes intertwined in the lymph node. Can you walk us through the biology and how we might harness these cells?

Krishna V. Komanduri, MD: Sure. I think the original studies came from work in 1970 that suggested that lymphocytes really needed two signals to get activated. The first one came through the T-cell receptor that recognizes the antigen, and the second one came through a costimulatory receptor. And initially, this was defined, but we didn’t know what those second signals were. We later realized that there was a molecule called CD28 that was necessary for driving that signal number 2 through T cells that helped them get activated, in addition to signal number 1. And then we realized really, over time, from the work of Jim Allison and others—and actually Carl June and Paul Martin when Carl was at the Fred Hutchinson Cancer Center—that there were multiple positive and negative signals that were present on the surface of T cells.

So, what we have learned and what really has been applied in clinical practice, first through the work that led to the FDA approval of ipilimumab in melanoma in 2011, was that—for example, CTLA4, which is a negative second signal receptor on the surface of T cells—an antibody directed against that could basically take the brakes off of T cells. In the context of ipilimumab, a T cell gets activated, and then the secondary negative signal through CTLA4 gets amplified unless that signal is blocked. When that signal is blocked, effectively, the brakes are taken off the immune response and the T cell can get activated in a greater way.

The first FDA approval was really for, again, ipilimumab, an antibody against CTLA4. And then we saw, following that, antibodies that regulated the interaction between a second receptor, called PD-1, on the surface of T cells, which binds to two ligands called PD-L1 (or PD ligand 1) and PD-L2. We know that through the work of others who are looking at the tumor microenvironment that these ligands for these negative receptors on T cells can actually be upregulated. Work in Hodgkin’s disease suggested that there was actually potential for genetic overexpression and higher regulation of PD-L1, which could then provide that negative response that could prevent tumors in the T-cell microenvironment from recognizing the cancer.

First, we saw approval of ipilimumab in melanoma, and then we saw the approval of pembrolizumab in melanoma and lung cancer. In 2015, we saw five approvals of single and combination therapies, and really the field is now exploding, as we saw here this year at ASCO. So, the data that Andre just talked about, for example, in Hodgkin’s lymphoma was very exciting.

Transcript Edited for Clarity