The Growth of Immunotherapy

[MUSIC PLAYING] Hi, everyone. You're watching Cancer in Context. I'm Dr. John Whyte, the Chief Medical Officer at WebMD. Today, I have a very special guest, Dr. Steven Rosenberg. He is the chief of the surgery branch and the head of the tumor immunology section at the National Cancer Institute, and one of the leaders in cell therapy. Dr. Rosenberg, thanks for joining me.

My pleasure.

Let's start off with explaining to our audience, we hear a lot about gene therapy, cell therapy, we're hearing about T cells. Can you walk it back a little for us and explain your research in terms of what you have discovered?

So let me try to put it in context, because my research deals with immunotherapy. That is, ability to stimulate the body's immune system to recognize and destroy a cancer. So to put that in context, we've had, over the last 100 years, three main ways to treat cancer. We have surgery, radiation therapy, and chemotherapy. And the optimal combined use of those three modalities can cure a little bit more than half of all people who develop cancer in the year 2021, but almost half of people will ultimately die of cancer. And we desperately need better treatments for patients with malignancy.

And we're now seeing the advent and the application of this fourth modality called immunotherapy. It doesn't use a scalpel or a radiation beam or a drug, but rather takes advantage of the body's own natural immune system to fight the cancer. And the kinds of treatments that I've developed involve identifying within the body the immune system cells called lymphocytes that can recognize the cancer. The body recognizes a growing cancer as foreign, but it doesn't recognize it strongly enough to reject it. And the goal of immunotherapy is to strengthen the immune reaction so that it can reject the cancer, in much the same way that we can reject viral diseases or bacterial diseases or transplants, ways that the immune system has of protecting the body from outside invaders.

But isn't part of the problem, though, Dr. Rosenberg-- you mentioned viruses and bacteria. To the body, they're foreign invaders. They come, for the most part, outside the body, and they look different. But sometimes, cancer cells look similar to normal cells. Isn't that part of the challenge of differentiating which ones are bad and which ones are good at the most basic level?

It's a very important part of the challenge. Now, the reason that the body can recognize a cancer as foreign-- and this is information just gained really in the last five years or so-- is that the body can recognize the products of the very mutations that cause the cancer. After all, cancer arises in most organs because there are dividing cells, generally in the ducts of the major organs, like the liver or the stomach or the pancreas or the ovary. Those cells are constantly turning over.

And as they turn over, they have to replicate DNA. And when that happens, mistakes are made. Those are called mutations. And those mutations now are foreign to the body because they're not present in any normal cell. They're the very mutations that cause the cancer in the first place. And so the body can recognize them, but they have very tiny differences. And the goal of immunotherapy is to try to take advantage of those differences to mediate cancer regression. And now, it can be done for some kinds of cancers, and it's getting better at a rapid rate of progress.

Well, let's talk about where we see the most success. It's in certain cancers-- melanoma, lymphoma. Is that right? Where are we seeing the progress, and where do we still need a lot more?

Well, the first progress was made in patients with metastatic melanoma, a lethal disease not responsive to standard treatments. And in fact, the first immunotherapy ever approved by the Food and Drug Administration in 1992 was based on our work utilizing a substance called interleukin 2. It's a growth factor of T lymphocytes inside the body. And those are the major immunologic warriors that are involved with rejecting bacteria, viruses, or tissue in the human body.

And so by giving interleukin 2 and stimulating those T cells, we showed that you could cause regression of widely metastatic melanoma. And that then led to a series of advances. Once we knew that and it got approved by the FDA and became widely used, we looked at what the exact nature of the cells in the body that recognize those, and could identify a kind of cell called a tumor-infiltrating lymphocytes. In some ways, what better place intuitively to look for a cell doing battle against the cancer than within the cancer itself?

And so in 1988, for the first time, we identified these tumor-infiltrating lymphocytes that were infiltrating into the stroma of the cancer. We could isolate them. We could modify them sometimes. We could enrich them and grow them to large numbers and return them to the body. And when one does that, you can mediate the regression of metastatic melanoma in over half of all patients.

And in about a third of those, it's a complete disappearance of melanoma that's ongoing now beyond 15 years, and likely curative. And these first experiments showed that, in fact, it was possible to use the immune system to treat cancer. And we're now in the process not only in my lab, but in laboratories around the world trying to extend those studies to other cancer types that cannot be cured by conventional treatments.

But viewers may be saying, Dr. Rosenberg, well, if this makes so much sense, right, use your own cells to battle tumor cells, why doesn't it work for all types of cancers?

Well, the problems are the ones that you, in fact, mentioned, the tiny difference, that sometimes in a string of amino acids that make up a protein that could be 500 long, there's only one amino acid that's different that makes that foreign. And the immune system just doesn't recognize it enough. So for example, if you look at tumor-infiltrating lymphocytes, only one in 1,000 of those cells actually recognize the cancer. Well, when it comes to the more common solid cancers, the epithelial cancers we mentioned-- lung, colon, and so on-- could be even less than that. And it's the difficulty in isolating those effector cells and growing them to the numbers that are required for therapy that represents the challenge.

Now, this is a new concept in cancer treatment, basically using the body's own cells. It's a living treatment. And so when we inject these cells and they can vigorously recognize the cancer, they can expand a thousand-fold inside the body. And that's how the immune system works. These lymphocytes patrol the body through the bloodstream. When they see their target, they extravasate out of the bloodstream into the tumor, where they attack it, and then, through the lymphatic systems, get returned and recirculate every 14 seconds, again patrolling the body to find these malignancies. But--

How do we know it's 14 seconds?

[INTERPOSING VOICES]

--studies that were done 50 years ago by injecting dye into a vein and seeing how quickly it then returns to other veins in the body. So the body is being patrolled by immune cells very, very frequently. And so identifying those cells represents the challenge. And we now, however, have published ways to effectively treat isolated patients with breast cancer, with colon cancer, with cervical cancer. It's a field that's rapidly expanding.

There are side effects. And we should point that out to viewers. And sometimes serious side effects. And we've seen that in the progress early on in your research. Some patients didn't do well early on. We still have some serious side effects, is that right?

That's absolutely true. Now, we're getting much, much better in learning how to avoid them and how to deal with them, but they are there. They're not so much due to the recognition of normal tissues, because the T cells recognize each unique products of mutations that are not present in normal cells. But when you have an immune reaction, the lymphocytes produce what are called cytokines. That is, molecules that have other effects in the body.

They can cause leakage of blood vessels, so that fluid extravasates into the body. They can cause fevers. And that's what happens when, for example, you have a common cold or a flu. It's not so much the virus itself that are causing the symptoms, it's the immune reaction against the virus that has these side effects. And that certainly occurs with the use of interleukin 2, and with the use of these T cells, as well.

Where do you think we'll be five years from now in this area of research? Some people are saying, you know what, this isn't the way to go, it's checkpoint inhibitors. What do you say in terms of you had a crystal ball, what will we be talking about in five years in terms of cell therapy?

Well, checkpoint inhibitors are not cell therapy. Checkpoint inhibitors--

No, as I point out, they're a different type of strategy.

Really different type of strat, but it is an immunotherapy. And it can be a very effective one for isolated kinds of diseases. Basically, the checkpoint modulators release a break on lymphocytes. Almost every physiologic system in the body, there are enhancers and inhibitors. And there are inhibitors of the immune system, as well. And the checkpoint modulators wipe out the inhibitors and let the activated influences work.

So the checkpoint modulators can be very effective in melanoma and some selected other cancer types, but they don't have much activity against the great majority of the solid epithelial cancers, at least not right now. Now, people are looking for new ones, but as of now, the common ones-- anti-CTLA4, anti-PD-1, these don't affect the solid epithelial cancers that are responsible for 90% of all cancer deaths.

So five years from now, what will it look like in terms of cancer treatment?

You know, I'm a surgeon, and there are continually improvements in surgical procedures. There are continual small improvements in chemotherapy, and then radiation therapy, as well, to try to target tumor tissue, leaving normal tissue unaffected. But none of those treatments are effective in the treatment of metastatic disease. And that's one of the characteristics of cancer. It's an uncontrolled growth, and the only cell in the body capable of starting in one location, but growing in another. And that's called a metastasis.

It's those metastases that are lethal to patients. And we have virtually no treatments for the solid cancers once they've metastasized that can be curable. And so immunotherapy has now shown it can do that in isolated circumstances. And I think that's going to improve dramatically over the next decade.

What about a vaccine for prevention? I know vaccines are involved in some treatments, particularly looking at receptors, but what about for prevention? Do you think that will occur in the next 10 years?

There's been an enormous effort to try to identify vaccines even targeting some of these mutational products that might be able to inhibit cancer growth. But those have been, as of now, universally ineffective as an immunotherapy, although there's a lot of work on ongoing, and hopefully some of it will eventually succeed. Right now, the best available treatments we have are treatments that can directly impact on the T cells. That is, the checkpoint modulators to release the inhibitory influences or the identification of these T cells that can then be administered as a living drug to patients. I think that's where the action is right now. And hopefully, someday, there'll be vaccines that can treat or prevent cancer, but I don't think we're even close to that right now.

We have a lot of students, young physicians that watch the program, and I wanted to ask you a little bit about your career in research. You've spent your entire career really researching cancer, finding new breakthroughs. There's a great line I read from your book, and you say you loved the night. And you almost didn't get married, you said, because you thought it would distract from your research. So it sounds like you're working all the time. I don't know if young people are going to be interested in that. But what do you say as we try to promote careers in science and technology and research? What's your message for viewers?

The most common question that I get from fellows who come to the lab to learn to do research deals with what qualities does it take to make progress, to make major progress in research. And of course, you have to be smart, but by the time you finish your degree and get a PhD, you're smart enough. But it takes two qualities that I've seen over the years in the many hundreds of fellows that I have mentored.

The first is you have to develop a passion for what you're doing. Now, passion is a good word, but it's a little bit of a cheap word. It doesn't really say exactly what it implies. To me, passion means the ability to immerse yourself in what you are doing so that, for example, when you're stopped at a red light or taking a shower, and you can't do anything, you just have to think, your mind is thinking about the projects that you're trying to solve, because the important problems in medical research are daunting. They're complex. You need a wide base of knowledge, and you need to be able to immerse in that knowledge so you can bring many fields together to try to make progress.

The second is a laser focus on the goal. Whenever you're doing research, experiments, there are always interesting things that come up, but you can't follow all of them. You have to have a laser focus on trying to answer the exact questions you set out to solve. And in this case, it's how do you cure patients with cancer. And so if you've got a broad base of knowledge, which is why I not only went to medical school, but got a PhD in biophysics before I finished my medical training, you need to immerse yourself in the field and in the research, and a laser focus on solving the goal.

That is good advice. And Dr. Rosenberg, I want to thank you for taking the time today. I want to thank you for all that you're doing. And you're being a pioneer in this type of research. It is saving lives, and at the end of the day, that's what really matters. So thank you.

John, it's been a pleasure. You're very welcome.

[MUSIC PLAYING]