How Melanoma Met its Match: Cancer Immunotherapy

TRANSCRIPT:

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Dr. Alicia Morgans: ​This is The Good News About Cancer. I'm Dr. Alicia Morgans.

Dr. Charles Ryan: And I'm Dr. Chuck Ryan.

Alicia: We're oncologists and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than there ever has been, and we're here to share that with you.

Chuck: In each episode of this show, we talk to one of our colleagues about a new development and cancer treatment or diagnosis. We'll break down what's new, why it matters, and how it points the way forward.

Dr. Jedd Wolchok: The first patient who I had the privilege of treating in, in a clinical trial, received ipilimumab, and within about three months, it became clear that she was having a very favorable response. And after just three months of treatment, which was the complete course, she had no evidence of disease.

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Alicia: You know, I am so happy that it's this time of year. It's starting to get warm out, I'm excited to go out, and go to the beach, and travel and do fun things. But when I think about warm weather, summertime, vacations, I also think about sunscreen and how we need to protect ourselves from things like skin cancer.

Chuck: Yep. Skin cancer needs to be top of mind during the summer, you are exactly right. You know, one in five Americans will develop skin cancer by the age of 70, and more than two people die of skin cancer every hour in the U.S. 

And most importantly, having sunburns doubles your risk – having five or more sunburns in your life – doubles your risk of melanoma. And melanoma is the skin cancer that can be deadly. 

Now the good news about melanoma – there's two pieces of good news. The first is that when detected early, the five year survival rate for melanoma is 99%. And it comes with, in some cases, minimal treatment. Removal by a dermatologist, sometimes some surgery, but we can all expect good outcomes if the skin cancer is detected, while it is still on the skin. The second piece of good news is that we have figured out how to harness the immune system to treat this disease.

Alicia: Yeah, that's what's so exciting here. This is really the development of treatments called immunotherapy, where we use our own immune system – the cells that live inside of us and protect us from intruders all day long – to understand that a cancer cell is not supposed to be there, and to unmask that cancer cell or take the brakes off the immune system so that our T cells and our other immune-type cells can actually attack the cancer cells and clear them out of the body.

Chuck: You know, I'm often asked about how immunotherapy works. And there's an analogy that keeps coming back to me, and that was the analogy of the mothership in the movie Independence Day. Think of the mothership like the cancer. It puts around a forcefield, and the missiles and the airplanes that try to get into it, think of them as the immune system. Well, the force field blocks those missiles and blocks those airplanes. 

But then Jeff Goldblum figured out a way to crack the code of the force field around the mothership, and the force field went down and the missiles and the airplanes were able to penetrate into the mothership and take down the aliens. And that's a little bit like what immunotherapy does. It basically takes down that protection barrier that the cancer has around it to prevent the immune system from getting in. So if that analogy works for you, great, if not, then that's okay too. 

To hear more about immunotherapy for melanoma and how it was discovered as an effective treatment, I talked to Dr. Jedd Wolchok. He is the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine at Cornell Medical School in New York City. He was one of the people who was pivotally involved in the development of many of these treatments against melanoma. So let's hear my conversation with Dr. Jedd Wolchok.

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Chuck: As we think over the past generation of good news about cancer and progress against cancer, melanoma comes right up to the top, I think, as one of these areas where we've made a lot of progress. I wonder if you could go back to the beginning of your career and talk about the way it was when you started. Tell us what you saw back then, and what the need was.

Jedd: So when I first joined the faculty at Memorial Sloan Kettering, the life expectancy of someone with advanced melanoma – melanoma that has spread beyond the site in the skin where melanomas usually start to a more distant location – the average life expectancy was between six and seven months. And there were certainly medicines that we could try to use, some chemotherapy, some early stage immunotherapies that could be used. But the efficacy was really limited. 

Most people died of their disease and most of those people who did die, did so within a fairly short period of time. And I think the most telling data that I convey is that the number of people alive with a diagnosis of melanoma for more than two years was less than 5%.

Chuck: Wow.

Jedd: And so that was the case, really going back decades until 2011. And then things began to change. 

Chuck: So, what was it that changed around 2011?

Jedd: There were really two areas of scientific research that began to mature around that time. The first was a deeper understanding of what were the molecular switches, if you will, that turned the immune system on and off. What were the pathways that regulated how forceful the immune system could be in recognizing cancer?

And the second was: what were the – inside the melanoma cell – circuits that told a melanoma cell how to divide? And so those were really critical steps that led to the development of immunotherapy for melanoma and targeted or precision medicine therapy for melanoma.

Chuck: So we haven't talked much about immunotherapy yet on the podcast. Obviously it deserves a lot of attention, because the immune system – for some reason – was turned off by the melanoma and that was really the cellular basis for why melanoma was one of the more deadly cancers, correct? 

Jedd: I think that certainly contributed. So, the immune system has these checkpoints, and so these immune checkpoints are pathways that keep the immune system under control. And some cancers have learned to co-opt these pathways, as a way to cloak themselves from the immune system.

Chuck: So what is it that makes skin cancer or melanoma a particularly sensitive entity to immune therapy?

Jedd: Melanoma in most, but not all, people arises because of damage to the skin from solar or sunlight. And that damage is reflected in mutations or genetic changes in the DNA of melanocytes, which are the pigment-forming cells in the skin that can give rise to melanoma. 

Now, with an accumulation of enough sunlight damage, the melanoma cell can actually begin to look different than the normal cell that it came from. Because the blueprint, the DNA, changes. And so the melanoma cell may start looking less like a normal human cell and more like something foreign, more like a bacteria or a virus, which the immune system is very eager to recognize.

So cancer, for many years, to an immunologist, was not able to be accurately classified as “self” or “not self.” It was really considered to be somewhere in between. And due to our ability now to sequence genomes of cancer cells quickly and relatively inexpensively, we know that that assumption was true, that some cancers look very much like the normal cell that they came from. And this is true of, say, pediatric cancers, where there is not the time available for a lot of genetic damage to occur. 

But some cancers, like melanoma, like lung cancer, like bladder cancer, where there is chronic exposure to carcinogens, which causes genetic damage. In the case of melanoma, it's sunlight. In the case of bladder cancer and lung cancer, it's the carcinogens in tobacco smoke. That is a very strong influence on the likelihood of immunotherapy working.

Chuck: And that's really one of the key facets of the success of immunotherapy is that it has really been best applied to these very cancers where DNA damage, mutations, inflammation, has been a key driver.

Jedd: Exactly right.

Chuck: So take us back to your situation personally, as a physician, when you began to see the progress starting to emerge, where was it? What were you testing? Take us back to that time.

Jedd: That would take us back just about 20 years to 2005, when I was introduced to an amazing scientist named Dr. Jim Allison, who was at the time being recruited to move from University of California, Berkeley to Memorial Sloan Kettering to become a leader of the immunology program. 

And Dr. Allison, who would later go on to win the Nobel Prize in 2018 for this discovery, was working with one of these cloaking pathways, called the CTLA-4 pathway, that he hypothesized was one way that the cancer could hide itself from the immune system. And he was devising ways to cut off these cloaking pathways temporarily, using antibodies, that would allow the immune system to run past this governance mechanism and hopefully outwit the cancer cells. 

And Jim developed an antibody that he drew some interest from the biopharma industry in, and the antibody had a very hard to pronounce name, called ipilimumab. And ipilimumab was the first of these immune checkpoint blocking antibodies to enter the clinic. 

It was explored in a few different diseases, including prostate cancer. But there were some early signals in clinical trials that maybe people with melanoma were responding to this drug. And so I became involved, as an investigator, in one of the initial clinical trials of ipilimumab. 

And as it happened, the first patient who I had the privilege of treating in a clinical trial, was a young woman, who was 24 years old at the time, whose body was quite heavily burdened with metastatic melanoma.

She volunteered for a clinical trial, received ipilimumab, and within about three months, it became clear that she was having a very favorable response. She ended up having a complete remission, and after just three months of treatment, which was the complete course at the time, she had no evidence of disease. 

That was really the beginning of the change of fortune for people with metastatic melanoma. 

Chuck: So that was ipilimumab by itself. And, you've gone on to create other treatments and other combinations and other approaches, and walk us through the progress over the next 10 years.

Jedd: So, you know, then this patient was treated in 2005. And her story is actually very well chronicled in a documentary about Jim Allison called Breakthrough. 

Chuck: Seen it. 

Jedd: Yeah, so, you know, in 2010, the data from the clinical trial that this patient volunteered for was presented at the American Society of Clinical Oncology meeting, showing for the first time that any drug could increase the life expectancy of someone with metastatic melanoma. First time that happened. 

And then less than a year later, the U.S. FDA approved that drug for melanoma. And that was great for two reasons. First of all, it showed that we actually could change the natural history of this disease. But also, um, it opened the eyes of the pharmaceutical community that immunotherapy was something that needed to be embraced and run with.

And it accelerated, I think, interest in other, immune checkpoint pathways. And the next one that was explored was called the PD-1 pathway, which is another one of these molecular brakes. And that gave rise to now, I would say, almost a dozen medicines that block that brake. And those medicines by themselves can work very well in melanoma and other cancers. They can be combined with ipilimumab as we did with melanoma. And they can be combined with chemotherapy, as has been done with lung cancer and some gastrointestinal cancers.

Now, if we fast forward, right, to 2025, we just published data from the 10-year follow up study, which looked at combination therapy of ipilimumab with one of the PD-1 blocking drugs, nivolumab, in melanoma. And in that study, the average life expectancy was close to 6 years. So we went from like six months to nearly six years. And the number of people alive for 10 years or longer was between 40 and 50%. 

Now, if we look at the number of people who did not die from melanoma – because when you follow people for 10 years, they will likely die of something else. And so we had the ability to look at a different statistic called melanoma-specific survival. And in our study, the melanoma-specific survival was more than half of people, were alive without dying from melanoma. 

Chuck: So do you have a sense of the number of individuals now who have been impacted in the U.S.? I know that there are about 100,000 new diagnoses of invasive melanoma every year in the U.S. But we must be translating now into the hundreds of thousands of years of life extension.

Jedd: I think you're absolutely right. So, you know, most people with melanoma are cured because of early detection and a simple dermatologic or surgical procedure. But there are about 20 percent of people – 20,000 of that 100,000, right – you know, may develop more advanced disease. And previously, nearly all of those people would succumb to the disease. So, you know, doing the math, I think you're right.

Chuck: Another fact that oncologists dream of. Hundreds of thousands of people with their families enjoying the holidays, living life –

Jedd: Living life!

Chuck: Because of the work that we've been able to do. So there continues to be progress. But there have even been newer treatments since the checkpoint inhibitors, treatments called TILs. There's now some really interesting data on vaccines to prevent the recurrence – maybe we want to talk a little bit about those.

Jedd: Sure. So, just about a year ago, the U.S. FDA approved a cellular therapy, which is the TIL abbreviation that you used. TIL stands for “tumor infiltrating lymphocytes.” 

And this was really the lifelong work of Dr. Steve Rosenberg from the National Cancer Institute, who was fascinated with the possibility of essentially separating white blood cells from a surgically removed melanoma metastasis, growing those white blood cells in the laboratory, and then giving them back to the patient like a transfusion.

And he toiled away, through many years of studies that were really only done, because of their complexity and intensity, at the clinical center at the National Institutes of Health,  to show that this could actually help. And it could actually help about 30 percent of people who have melanoma that did not respond to checkpoint inhibitors.

And that technology was eventually licensed to a pharma company and approved by the FDA about a year ago. And so we now have an intervention that we can offer to people. It's still quite complex. It requires inpatient care. It requires a surgery. It has, um, some very serious uh, toxicities like any treatments for cancer can have. But we now have that on the list of standard treatments as well. 

On the list of experimental options, you mentioned vaccines. And that's actually how I started my career, was trying to develop vaccines for melanoma. And the field has come a long way, although we do not have any approvals yet for human melanoma vaccines. There is an ongoing clinical trial looking at what's called a neo-antigen vaccine, given along with the checkpoint inhibitor, to people who have had melanoma removed surgically but are at high risk for it coming back. 

So the way that this treatment works is that a tumor specimen, either a biopsy or an actual surgical specimen, is analyzed with gene sequencing to identify all of the mutations that are present in the tumor cells. Then a computer program picks out the specific genetic mutations that are thought to be the most immunogenic, and a synthetic mRNA vaccine is created – the same technology that gave us the COVID vaccines – is created for each individual patient and administered to that patient. 

And believe it or not, all of that gene sequencing, the computer analysis, and the manufacturing can take place within a few weeks. And this neoantigen vaccine I think is a very clear example of how far science has come to deliver new therapies. It’s just extraordinary.

Chuck: It is amazing. And, you know, the other thing about melanoma that perhaps makes it a unique substrate, or a unique target for this approach, is the fact that melanoma has – if I'm not mistaken – kind of a unique barcode. Every individual patient has his or her own unique set of mutations that may occur because of the randomness through which UV light will damage DNA.

Jedd: That's exactly right.

Chuck: So, so you, there will never be an off-the-shelf vaccine that everybody gets for melanoma because this is a bespoke, or it's a custom made, vaccine around your individual mutation pattern.

Jedd: That's exactly right. 

Chuck: It is a fascinating area and we'll look forward to that, hopefully the maturation of that data. I've been following that with some enthusiasm for a couple of years now. 

So for people listening now who are looking forward to the future, what do you think they can expect for future melanoma patients, should they need immunotherapy or other therapies?

Jedd: I am very, very optimistic about the future. I think that the amount of knowledge that we have gained about melanoma biology, about the biology of the immune system, about how quickly we can gain knowledge about an individual person's cancer, the speed with which we can develop personalized therapies…It's really impossible not to be hopeful about what the next generation of treatments will look like.

And importantly, I don't think that this is limited to melanoma. I think this, you know, this hope can be extended to other diseases because our focus on the mechanisms of what drives a cancer cell to divide, and what prevents the immune system from seeing cancers, are pretty universal, in terms of being applied across different diseases.

Chuck: I think we may need to make that the subtitle of our podcast, “impossible to not be hopeful.” I love that. Very nice use of a double negative there. Dr. Jedd Wolchok, thank you so much for joining us on The Good News about Cancer with a really good, good news story. 

Jedd: Thanks again for the invitation. 

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Alicia: What great news. And everybody, wear your sunscreen!

Chuck: Thanks for listening to The Good News About Cancer. I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York.

Alicia: And I'm Dr. Alicia Morgans at Dana-Farber Cancer Institute in Boston. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work.

Chuck: Thanks to Lilly for support of the show. Our production partner for this series is CitizenRacecar. This episode was produced by Anna Van Dine with post-production by Alex Brouwer.

Alicia: And there's a whole lot more good news to talk about, so make sure you subscribe to this wherever you listen to podcasts. And if you like the show, share it with someone you think might find it interesting.

Chuck: We will be back again soon with more good news about cancer – and we'll see you on the beach.