Transcript:Mark A. Socinski, MD: Let’s talk a little bit about the various choices that we’ve made—maybe some history and pertinent to modern times—in terms of the mechanism of action. You’ve mentioned a couple of the cytokines—IL-2, gamma interferon. How are they helping the immune system to fight cancer?
Howard L. Kaufman, MD: In general, we don’t fully understand interleukin-2. IL-2 is approved for the treatment of metastatic melanoma and renal cell carcinoma, and there’s no question it can lead to durable responses. And now that we’ve had a chance to follow patients for 15, even 20 years, these probably are really cures in these patients. We think that the main way that IL-2 works is it really acts as a T-cell growth factor. There are IL-2 receptors on the surface of T-cells, and it leads to their growth and proliferation, and when you have an effector T-cell that can recognize the melanoma cell or kidney cancer cell, you get a good response.
I think the dual-edged nature of IL-2 is that it also activates cells that are called regulatory T-cells. These regulatory T-cells also contain IL-2 receptors and can expand up, and they actually block immune responses. We don’t really understand why, in some patients, those effector cells will be preferentially expanded and why in some patients the regulatory cells will expand. But there’s a lot of research going on now to really try to understand that, to try to block the regulatory cells and really let IL-2 work on the effector cells.
Other cytokines in development—for example, interleukin 15—seem to be more preferential for those effector cells, for the memory cells, the kind of cells we want to see to eradicate a tumor. And so that’s going to be interesting, as this is being tested in many clinical trials right now.
Mark A. Socinski, MD: John, probably the most exciting agents we’ve seen—and across a number of solid tumors—have been the monoclonal antibodies to a specific target—CTLA-4, PD-1, or PD-L1. Talk us through the monoclonal antibody and what’s going on there.
John V. Heymach, MD, PhD: So, this work is really probably the single biggest breakthrough that has led to immunotherapy being a modality that we consider a standard now, just in the last couple of years. It had been observed that, very often, T cells could be present, but were being inhibited from fighting the cancer, and it wasn’t understood for a long time why that was happening. And, as Howard mentioned, you have different types of T-cells. You have T-regulatory cells that we think help keep the breaks on and effector T-cells that do the heavy lifting in killing T-cells.
It was finally understood—and Jim Allison was one of the pioneers, although a lot of others have contributed to this—that there were things that were inhibiting T-cells from doing their work. And we now call these the checkpoint factors. What checkpoint inhibition means is that a T-cell interacts with a ligand—there’s a receptor on the T-cell that would have, for example, PD-1—and then on an antigen-presenting cell or a cancer cell, there would be a ligand PD-L1 or PD-L2. And when those two interacted, that would stop the cell from attacking.
The first one discovered was CTLA-4, and the first monoclonal antibody that was clinically approved for blocking this is called ipilimumab. So, ipilimumab blocks CTLA-4; it essentially took the breaks off the immune system, and it got those T-cells attacking whatever its target was once again. Now, this is a system that’s normally in place to help prevent the immune system from becoming overzealous, from keeping things like autoimmune reactivity at a minimum. It’s not surprising that one of the consequences to taking the brakes off is you do have an increase in autoimmune consequences, and we do that in a variety of different ways.
But this is the concept now: first with CTLA-4, blocking that enhanced tumor responses; then PD-1 or PD-L1, blocking either one of those. And now we have a long list of other checkpoint factors that are potential targets. And so, in upcoming years, we’re going to see a lot of different drugs blocking those others. But really CTLA-4 and PD-1, PD-L1 access are the two that are cornerstones for what we’re doing right now.
Mark A. Socinski, MD: Howard, tell us your perspective on therapeutic vaccines and how they may play a role.
Howard L. Kaufman, MD: I think a lot of the core of how T-cells work are they’re really designed to recognize an antigen. And so the concept of vaccination is that if you knew what the antigen is that the T-cell is seeing, you could simply immunize the patient and get an immune response to it. While I think that makes sense, I don’t think we really understood all of the other factors that can influence the T-cell response. And the success of the checkpoint inhibitors, of course, has really put them front-and-center in the field.
One of the interesting findings in some of this work has been that the mutation burden may correlate with good response to these checkpoint inhibitors, and that suggests that with more mutations, there may be more antigens available. And so the idea that we could come back, maybe with a vaccine, and help these responses along is gaining some momentum right now. I think the field suffers from a lot of negative vaccine studies that were done early on because we didn’t really understand what was going on in the tumor microenvironment. And if you really look at some of the more carefully done trials, there was evidence that you could generate T-cell responses with these vaccines. But probably when they get close to the tumor, they just were being suppressed or energized and really couldn’t do their job. So, I think we’re going to see more with vaccines in the future, and we’ll have to put them into the clinic and test them to really see what their full potential is.
Mark A. Socinski, MD: Any hope of a patient having a customized vaccine for their cancer?
Howard L. Kaufman, MD: It’s a good question. The idea is, if we could somehow logistically figure out what mutations are in a given cancer. And so the developments in precision medicine, of course, are very interesting to us because you can now rapidly survey the tumor genome and see what’s happening. And if we could develop a vaccine approach that could target some of those new antigens, it might be very interesting to see if that’s not more effective. Steve Rosenberg has done some work recently trying to do that—where he’s been able to generate a T-cell to one of these new antigens—and, of course, has seen regression in one patient so far.
Mark A. Socinski, MD: That’s all you need for a start.
John V. Heymach, MD, PhD: Yes, and that’s right. You know, as Howard is saying, this is the interface of genomic medicine and the immune system. And you know you can imagine now that we’re starting to get all this next-generation sequencing data, where we’re identifying mutations of hundreds and hundreds of genes. What you’d love to be able to do is not only target mutations with things like tyrosine kinase inhibitors, but if we predict this would be an antigen, this particular mutation, and you’ve got this HLA (human leukocyte antigen) type, essentially take off the shelf T-cells and give them to a patient. I think that would have been “pie in the sky” 5 or 10 years ago, but we’re taking steps that make that a more and more concrete possibility in the near future.
Transcript Edited for Clarity