More Options For Cancer Immunotherapy
Tumors are masters of disguise. Unlike a virus or bacteria, a tumor’s cells are our cells. They produce molecules that can block immune system cells from recognizing them. Often, they mutate to shed other molecules that might flag the cell as unhealthy. These are some of the biggest challenges when fighting cancer.
The field of immunotherapy—teaching our immune system to recognize cancer—is burgeoning with solutions to this problem. The FDA has approved therapies for cancers, such as melanoma and lung cancer. But problems remain. Not every patient responds to immunotherapy. In melanoma, for example, only about 30 percent of patients given immunotherapy see significant tumor shrinkage.
One approach might be to enlist more parts of the immune system in the fight. For example, “natural killer” cells can rapidly detect and destroy stressed cells. Writing in the journal Science last month, oncologist Kai Wucherpfennig and other researchers describe an antibody that can prevent tumors from hiding from these immune responders. They say this may also have fewer side effects than the therapies that target T cells.
Wucherpfennig, director of the Cancer Immunotherapy Center at the Dana Farber Cancer Institute, explains this approach and others. He’s joined by University of California, San Francisco immunologist Lewis Lanier, who has been studying natural killer cells since the 1980s.
Lewis Lanier is Professor and Chair of Microbiology and Immunology and Director of the Parker Institute for Cancer Immunotherapy at the University of California-San Francisco Medical School in San Francisco, California.
Kai Wucherpfennig is Director of the Center for Cancer Immunotherapy Research at the Dana Farber Cancer Institute in Boston, Massachusetts.
IRA FLATOW: This is “Science Friday.” I’m Ira Flatow. Chemotherapy has been a standard practice for decades, but because it kills healthy cells as wild as cancerous ones, it has many side effects. It’s now becoming clear that our immune systems are one of the best weapons we have. Our bodies come with an array of tools for removing unwelcome visitors. But tumors are also adept at telling our t-cells and lymphocytes to move along, there’s nothing to see here.
So even as the field of immunotherapy advances, only a fraction of the patients respond, about 25% from melanoma, for example. And there can be an intense autoimmune backlash where the immune system starts to attack the rest of the body and not just the cancer. So what if you could cure your cancer, but at the cost of diabetes? That’s not a great idea. Well, like in any war, the one against cancer is sort of a chess game, learning to outsmart, out think, out move your enemy. Now there is one approach, try to activate more kinds of cells in the immune system to attack the tumor, use more of the tools on that cellular Swiss Army knife.
And new research published in Science last month explores just that, using antibodies to bring our body’s natural killer cells into the fray. Here to explain the approach and what lies ahead for cancer immunotherapy is Dr. Kai Wucherpfennig, director for cancer immunotherapy research at the Dana-Farber Cancer Institute in Boston. Welcome, Kai.
KAI WUCHERPFENNIG: Thank you so much for having me.
IRA FLATOW: You’re welcome. Dr. Lewis Lanier, professor and chair of immunology and microbiology at UC San Francisco, would to “Science Friday.”
LEWIS LANIER: Thanks. Happy to be here.
IRA FLATOW: Nice to have you. Kai, if our immune system is so great, how do the tumors– give us a little primer on how the tumors manage to hide so well from it.
KAI WUCHERPFENNIG: So the interaction between tumors and immune cells is extremely complex. And the tumors that actually become clinically apparent, that become the real problems of medicine, actually have evolved for a long period of time with the immune system. And you can think of it as a struggle between the tumor cells and the immune system and some tumors manage to evade. It’s essentially an evolutionary war that is going on and sometimes the tumors win. And so what we’re trying to learn is how to outsmart the immune system and whether we can turn that against the tumor.
IRA FLATOW: Usually, the immune system is able to recognize a foreign cell, right, and work toward removing it. But from the way I understand it, the cancerous cells are able to get rid of or cover up the flag that tells the cells, we are cancerous?
KAI WUCHERPFENNIG: Well, it’s actually very interesting. The immune system is incredibly adept at recognizing foreign invaders, for example a virus. And that’s because all of the proteins in the virus are distinct from human proteins. So it’s actually fairly straightforward for the immune system to identify the virus and to kill the infected cells. Now, tumor cells actually evolve from our normal cells. So in many respects, they’re actually similar to normal cells and so it becomes a much more complex problem of distinguishing the tumor cells from the healthy cells and when we do immunotherapy, how we stimulate immunotherapy without damaging healthy cells at the same time.
IRA FLATOW: So tell me about your work. Your work does a nifty trick preventing the cancer cells from hiding?
KAI WUCHERPFENNIG: Yes. So our work actually builds on the pioneering work of Dr. Lanier. So Dr. Lanier actually discovered a very important mechanism that allows immune cells to eliminate stress cells in the body. So stress cells can be infected cells or tumor cells. And so essentially, what these cells do is they put up molecular flags and that allows cytotoxic cells in the immune system to kill these stressed cells. It’s a very powerful immune defense mechanism.
But in many human cancers, tumors evade this process. And so what they do is they literally cut these immune recognition molecules off the cell surface and then the tumor cells become less visible to the immune cells. So what we did was to figure out how we can prevent this cutting of these immune stimulatory molecules on the cell surface. And we found that this elicits a strong anti-tumor immune response.
IRA FLATOW: Did you find this working in people?
KAI WUCHERPFENNIG: We found this working with human cells. This was actually inspired by a clinical trial performed by my colleague, Glen [INAUDIBLE], at the Dana-Farber. And then we developed antibodies, tested them on human cells and human immune cells. Then we moved it into an animal model to look at it in the context of a fully functioning immune system. And then we actually developed a humanized model to check whether, again, it works with human cells and with human tumor cells.
IRA FLATOW: Dr. Lanier, tell us about these natural killer cells, how they fit into the bigger picture of our immune system.
LEWIS LANIER: OK. Well, natural killer cells were discovered back in the 1970s. And at that time, it was shown that if you take some of your blood, put it in a plastic dish with cancer cells, they can kill them. So we’ve been trying to understand how that happens and how that operates. About 20% of your white blood cells, in fact, are these natural killers. They have an intrinsic ability to destroy cells that are either infected by viruses, I think that’s why they were really evolved, or the tumor cells also become stressed like virally infected cells and can put up some proteins or flags on the surface to allow them to see the cancer and kill it.
And they work really quickly because you already have about 20% of these cells in your bloodstream. So I call them the Marines. They’re the first ones on the beach to take out these cells which look abnormal. So the system that Kai has really made a great new discovery about is a way to keep the cancer cell from getting rid of those stress proteins, keep them on the surface so these killer cells can go in and attack and get rid of the cancer cells before it’s game of hide and seek. A lot of tumors do display these stress proteins, but then say, aha, I can evade these killer cells if I cut them off and make them soluble and make them not be on my surface so I’m invisible.
IRA FLATOW: I think the first time we were all in the public heard about immunotherapy was when President Carter talked about it and his run-in with cancer. And then we heard the word immunotherapy helping remove the cancer from his body. And when people I think erroneously said he was cured. But now it seems to be progressing and we hear news about it more often. How fast has the field to of immunotherapy grown in recent years? As I say, I still remember when I was a novel idea of a kind.
KAI WUCHERPFENNIG: So this is one of the most dynamic areas of cancer research and actually for all biomedical research. The speed of discovery and clinical translational is extremely rapid. There are more than 1,000 immunotherapy clinical trials ongoing right now and there are a lot of interesting ideas. The most advanced approach are these checkpoint blockers. So these target breaks in the immune system. And these antibodies now are approved for a number of different cancers ranging from melanoma to lung cancer, renal cancer, bladder cancer, lymphomas, and many other cancers.
IRA FLATOW: But how successful, what is the cure rate on these?
KAI WUCHERPFENNIG: So I would measure the success rate in the durability of the therapy, and this is why this is such a game-changer. So with conventional cancer therapies, be it radiation or chemotherapy, you induce a transient response. The cancer comes back, it becomes even harder to treat. And so the reason immunotherapy is a game changer is because a substantial number of patients have durable responses that last for many years. And so what it teaches us is that when we elicit the right type of immune response, it can actually keep a cancer in check for a long period of time.
Now, that’s the upside. The problem is that it is still not effective in the majority of patients. And there are a lot of good reasons for this, and a lot of these relate to these evasion strategies that Lewis just mentioned that cancers have ways of evading an immune response, for example, by cutting immunostimulatory proteins from the cell surface. And so what many labs, including mine, are doing is to figure out what these evasion mechanisms are and to develop clever molecular tricks of how to deal with them.
And so I think what many of us are seeing is that this is a very rapidly evolving field. There are a lot of fantastic ideas and they get translated much more quickly than in the past into novel clinical trials.
IRA FLATOW: So when will we see a higher– I know you talked about what you mean by success rate in mapping the people that it works in and it works for years. But if we’re talking about a 25% rate in melanoma patients, how do we get that number up in all the cancers?
KAI WUCHERPFENNIG: So to put melanoma data into perspective, so this is in patients with advanced metastatic melanoma. In the past, almost all of these patients would die. And now and this disease that used to be very deadly, a substantial number of the patients actually become long-term responders or in essence cured. So the way we get the response rate up is by improving the immune response that exists, but also bring in new players of the immune system into the game. And this is why bringing in k-cells into the attack is actually very important.
IRA FLATOW: The killer cells, yeah.
KAI WUCHERPFENNIG: Yeah. so the killer cells, the natural killer cells. So the current immunotherapies work by targeting a certain type of immune cells called the t-cell, and t-cells are very powerful. But many advanced cancers find ways to evade and attack by a t-cell, but they may still be sensitive to an attack by a killer cell. So the way I think about it is that the immune system is like a Swiss Army knife. It has many different tools and when you have a complex problem like an advanced cancer, you want to use multiple tools at your disposal and figure out what is the most sophisticated way of them working together the way they should be.
IRA FLATOW: I get it. Dr. Lanier, I just wanted to get to another problem with ramping up the immune system is the side effects mentioned before– type 1 diabetes, but problems, the immune system even attacks the heart. Are we learning how to prevent these side effects?
LEWIS LANIER: Well, there’s a lot of studies going on right now to be able to predict which people are going to get the side effects because the majority don’t get the side effects. The majority have an anti-cancer effect without causing that. But since people are very genetically heterogeneous, we’re going to be able to look in the future, I think, and can say, well, if we use this therapy, you’re at higher risk of getting diabetes or thyroiditis other side effects. The other thing that I think will happen is we start to be more precise.
Right now we’re using a blunt tool of taking the brakes off of all of the immune system checkpoints so that if you have t-cells that see the cancer in and allow them to go loose, that’s good. If you are predisposed genetically by having predispositions in your family for autoimmune disease and you let those cells go, it’s bad. However, if we can now only engage the cells that can see the cancer but not see you, that will then make a huge leap forward. And I see that happening. We’re getting smarter about this.
There’s many studies going on right now about how to make those predictions and also how to manipulate the killer cells, both with drugs but also genetically to make them more specific for the cancer.
IRA FLATOW: I’m Ira Flatow. This is “Science Friday” from WNYC Studios talking about cancer immunotherapy. Do you get discouraged when you do your research about how slow it’s going, or do you feel optimistic about how fast it’s going?
LEWIS LANIER: I think scientists have to be optimistic.
IRA FLATOW: I mean, by nature.
KAI WUCHERPFENNIG: Yeah. So my answer to this is that I mean, so I’ve done this for more than 25 years. And so the science moves so much faster, the progress is so much faster than it was even five to 10 years ago because our tools have gotten so much better. We have the whole genome sequence at our disposal, we have advanced techniques for interrogating immune cells both in humans and in animal models, and we also have new types of therapeutics. And so in my lab, things are literally exploding right now.
I mean, we have a number of approaches that are advancing toward clinical trials. And I see this across the field that there is remarkable acceleration of progress. That said, cancer is a very difficult problem. And it’s important to remember that there cancers for which there has been no significant therapeutic advance for 20 or 30 years, so for example, glioblastoma or pancreatic cancer. So what I’m trying to say is that when you get immunologists on the air, they always say how great immunotherapy is and I’m certainly one of them.
But I also want to say that cancer is a very challenging problem. We’re not going to fix it in the next two to five years, but we are definitely making a lot of progress.
IRA FLATOW: Would you agree?
LEWIS LANIER: Yeah. I would certainly agree. This is the most exciting time in my life. I’ve been working on cancer immunology since I was a PhD student in the 1970s and curing mice back then of cancer. It’s remarkable that it’s now working in people. People, as you mentioned, one in four who were going to die of melanoma are now living 10 years or more. So we’ve seen such great progress. I see no reason– we’re even getting smarter now and having better tools, as Kai said, to be able to make this work much better. So I’m optimistic.
IRA FLATOW: So part of the treatment is just to keep people alive long enough to be around for the new tools that can be used.
KAI WUCHERPFENNIG: That that’s definitely part of the game, yes.
IRA FLATOW: And it’s good to see that you’re both optimistic. And we will follow this because I read about this– we read the journals every we can see new studies coming out and that’s why I wanted to have you gentlemen come on and talk about it. Thank you both for taking time to be with us today.
KAI WUCHERPFENNIG: Thank you.
IRA FLATOW: Dr. Kai Wucherpfennig, director for cancer immunotherapy research at the Dana-Farber Cancer Institute in Boston. Dr. Lewis Lanier, professor and chair of immunology and microbiology, University of California in San Francisco. My cold is getting the better of me.