The Immune System and Cancer Pathogenesis

Transcript:Mark A. Socinski, MD: Hello, and thank you for joining us today for this OncLive Peer Exchange panel discussion on the topic of “Immunotherapy Use in Advanced Solid Tumors.” Immuno-oncology is rapidly evolving, focused on novel immunotherapies, many of which are proving to induce durable responses and improve overall survival in multiple cancers. Important questions center on how best to use immunotherapies that rely on both active and passive mechanisms, including as part of combination therapy. In this OncLive Peer Exchange discussion, I’ll be joined by a panel of experts who will focus on the use of immunotherapies in advanced solid tumors of the lung, bladder, head and neck, kidney, as well as melanoma.

My name is Dr. Mark Socinski, and I’m a professor of medicine at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania. I’m joined today by Dr. Dean Bajorin, a professor of medicine and medical oncologist, and the Frederick R. Adler Senior Faculty Chair of Memorial Sloan Kettering Cancer Center in New York City; Dr. John Heymach, professor and chairman of the Department of Thoracic and Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas; Dr. Howard Kaufman, associate director and chief surgical officer at Rutgers Cancer Institute of New Jersey in New Brunswick, New Jersey; and Dr. Jared Weiss, assistant professor of medicine in the Division of Hematology and Oncology at the University of North Carolina School of Medicine in Chapel Hill, North Carolina.

Gentlemen, thank you for joining us. Now, let’s begin. We’ve seen really a revolution in therapy with the advent of immunotherapies, and I really wanted to start, John, with you and just have you talk us through the immune system and how it relates to cancer pathogenesis and those issues.

John V. Heymach, MD, PhD: This is, I think, without question the most exciting area that’s happening in oncology now, and we’re already seeing a revolution in how we treat all these different cancers—including lung cancer—that we’re talking about today.

The first thing about the immune system is it really plays a double-edged sword when it comes to cancer. On one hand, it’s been known for a long time when the immune system is overactive and you’ve got inflammation that inflammation can cause cancer. For example, people that have a lot of inflammation in their lungs are more prone to get cancer, or inflammation in their pancreas or liver or other organs. So, in that sense, the immune system can be pro-cancer forming. But what’s really exciting is that we’re now learning how to harness it to fight cancer. And we’ve known for some time that the immune system plays a role in keeping cancer in check, and there is evidence for this when people are immunosuppressed—for example, people with AIDS. One of the leading causes of cancer, or one of the leading causes of death, among people that have profound immunosuppression like that are cancers that arise when you lose that immune surveillance. We recently reported that it plays a key role in preventing tumor metastasis from coming out. So, when cancer cells enter the bloodstream, you need the immune system to hold them back.

In fact, there’s good evidence that if it wasn’t for our immune systems, we would get lots of cancers. And there are little cancers that are being helped and checked all the time in the body. But what’s really exciting, that’s happened in the last couple of years, is we finally have started to figure out how to harness the immune system to fight cancers that are already there. And you know, one thing I explain to my patients—and when you think about it—any tumor that has grown up to be a cancer that’s affecting a patient is one that’s already figured out a way to avoid the immune system. Otherwise, it never would have grown to be a tumor that the patient is having symptoms from.

And so the question is, can we figure out ways to uncover the tumor so the immune system could recognize it, stimulate the immune system? There’s a variety of different approaches that have been taken, and we’ll talk about some of those today. I’ll just give a couple of sweeping comments about the immune system.

The immune system has different arms. There’s one we call innate immunity, and then there’s adaptive, or what we call acquired immunity. And the acquired immunity, or the adaptive immune system, is really meant to fight pathogens that come in. So, when we get a bacterial infection or a viral infection, this is the response to that, and the key thing about adaptive immunity is there’s memory. When we think about two legs of this, we think about T lymphocytes and B lymphocytes—and they also make things like antibodies that form what we call the humoral arm. We think of the cellular arm and the humoral arm of the adaptive immune system.

And, really, there’s approaches for fighting cancer that use all these that try to harness B-cells, T-cells, antibodies, and so forth. One thing I’ll tell you is the immune system is complicated. Like I said, it’s got a lot of different parts to it. So, this is going to be something that keeps cancer doctors busy, I think, for years and years to come—figuring out how to harness it. And we’re just touching the tip of the iceberg right now.

Mark A. Socinski, MD: I think much of our understanding of the immune system currently…when we were all in medical school, this was not known at the time. So, Howard, I want to ask you, in terms of the evolution of immunotherapy over the past 30 to 40 years, it really has been an amazing development of…

Howard L. Kaufman, MD: I think the only word is “historic.” I think that the concept of using the immune system has been around for almost 100 years, if not a little bit longer. But the success that we’re seeing now is relatively recent. I think it’s important to remember that many of the immunotherapy approaches we have; they really manipulate the immune system. But the drug that we’re really dealing with is the T-cell. And I think the reason that we’re seeing the success now is that we really understand some of the basic principles of what regulates T-cell activity. And it turns out that it was not only important to understand how we turn on the T-cell and stimulate it, but also to understand that cancer’s already figured out how to shut it down. So, many of the new approaches, such as the T-cell checkpoint inhibitors, are really designed to prevent that turning off of the T-cell, and that really opens up the door then for what has turned out to be pretty interesting and dramatic immune responses.

The other thing that I think has happened is we used to think of immunotherapy as something that would be useful for melanoma patients, maybe some kidney cancer patients, but not for other cancers. I remember when we used to consider melanoma the immune-genetic tumor, and we would see occasional responses with things like IL-2 and interferon. And even those were thought to occur in a relatively small number of patients.

But I think, now that we really understand how these T-cells are working, the real advance has been that this seems to work in many, if not all, types of cancer. And we understand that each cancer may require a different approach, depending on what’s going on within the tumor microenvironment and other things within the patient. And I think—as you’ve alluded to, the inflammation concept— I think we now can understand that inflammation can occur in really two flavors.

There’s a good acute inflammation, which can get us a good immune response. But there’s a bad chronic inflammatory condition that can actually promote tumor growth. And we are now thinking about how to really deal with both sides of that coin. And the prospect for combinations, I think, is what we’re all very excited about because it does look like—certainly in the animal models and now in some of the early clinical work, especially in melanoma and, as we’re going to see this year at ASCO, in lung cancer—that when you start combining these agents together, we’re beginning to see much better responses.

Transcript Edited for Clarity