An article from Scientific American.
The Albert and Mary Lasker Foundation.
The scientist who helped deploy our own immune system’s power to beat back cancer snagged one of this year’s Lasker Awards, a prestigious group of medical prizes commonly known as the “American Nobels.” James Allison, a Houston-based immunologist, had already won a Breakthrough Prize in Life Sciences and more recently he scooped up the Louisa Gross Horwitz Prize, an award that honors outstanding research in biology or biochemistry.
His newest accolade is designed to recognize researchers whose contributions have improved the clinical treatment of patients. Allison’s seminal work focuses on a protein called CTLA-4, which reins in T-cell activation in the immune system. By suppressing the molecular brakes that would otherwise block CTLA-4, Allison found he could unleash the T cells to combat tumors. That discovery helped fuel new cancer treatments including immunotherapy for metastatic melanoma that has been shown to extend patients’ longevity by as much as a decade (median life expectancy for metastatic melanoma is under one year).
Another Lasker award, which honors basic research, will go to Stephen Elledge and Evelyn Witkin for their work unraveling the fundamentals of how the body detects and corrects for DNA damage. Doctors Without Borders will also receive a Lasker Public Service Award for its humanitarian work responding to Ebola in West Africa.
Allison, chair of the immunology department at the University of Texas M.D. Anderson Cancer Center in Houston and executive director of its research center on immunotherapy, spoke with Scientific American about the future prospects and limitations of immunotherapy.
[An edited transcript of the interview follows.]
In the mid 1990s you helped pioneer the field by finding that if a key molecular brake system could be sidelined, then the immune system would be able to more effectively kill cancer cells. What makes immunotherapy so different from other cancer treatments?
Traditional cancer therapies are typically drugs that attack the mutations causing the cancer. That’s a good idea but there are a few problems there including the fact that the tumor becomes resistant to the drug.
What we call “checkpoint blockade” therapy – the immunotherapy we’re talking about here – differs in a few ways. We get the immune system to attack the process of carcinogenesis itself. Checkpoint blockade actually employs T cells to affect tumor cells. T cells detect mutant or foreign peptides on the surface of cells to give the immune system an idea of what is going on. With lung cancer or melanoma there are hundreds of thousands of mutations. So with checkpoint blockade T cells will recognize new peptides that shouldn’t be there. Then, once you have T cells, unlike with chemotherapy or radiation, there is memory. You have T cells for the rest of your life, so if the tumor reoccurs those T cells can mobilize themselves again against the tumor. The last difference is adaptability. Since your immune system is a dynamic thing, if the tumor changes, the immune system can change its response as well.
Before the mid 1990s there was still some history with immunotherapy.
Yes, the fact that the immune system could be used to treat cancer was first proposed in 1909 by Paul Ehrlich and he had the idea about antibodies. He thought the immune system had antibodies that could eliminate tumors. The question was what antibodies could we use? The reason I think there is so much excitement about checkpoint blockade is it’s relatively easy. You inject an antibody into a person. And you target the immune system and unleash it and there are many different ways to do it that can be combined. It’s the renaissance of immunotherapy. I would say it’s the rebirth of immunotherapy rather than it’s new.
Sometimes cancer patients treated with immunotherapy will have their tumors initially expand. That underscores how difficult it is to measure progress during immunotherapy. Do you see that as one of the largest challenges in the years ahead?
Not really. It caused some concern initially because people thought the tumors were growing faster. Now we know it is pseudo-progression. The tumors are actually filling up with T cells, so if you biopsy them you find there are no living tumor cells in there. It’s actually T cells. This did confound the field for a while because with traditional therapies an expanding tumor is a sign of failure. So we have to evaluate success differently. There are two ways it’s been dealt with: one is looking at the tumor again at a different time point. The other way is to look at overall survival.
At one point, scientists thought that interferon was going to cure cancer, as were monoclonal antibodies, for that matter. Do you think unrealistic hopes are mounting for immunotherapy?
No. I think we are far enough along with it, with over 50,000 patients treated—some who are 10 years out now—that our hopes are not unrealistic. It’s clear this is not going to cure every patient, but treatments that include immunotherapy are more effective than other options. This field is expanding very rapidly. The immune system is such a powerful thing that needs to be tightly regulated. We have revealed how to take advantage of it to treat cancer.
Do you think any particular cancers will not be treatable with immunotherapy or will not have immunotherapy as part of a treatment package to combat them?
Theoretically, since we are not treating the cancer, the cancer doesn’t really matter.
Melanoma and lung cancer, where most of this work has been done, both have a lot of mutations. They have hundreds of thousands of mutations per cell and it’s the mutations the immune system recognizes. When you get to cancers like breast, prostate and kidney, which have smaller numbers of mutations, the drugs aren’t quite as effective. Our job now is to figure out how to make immunotherapy effective against those tumors with small numbers of mutations. I think there may be some that don’t respond to [immunotherapy] but I’m pretty optimistic that we will be able to deal with a very large number of types of cancer.
With the soaring costs of some new drug treatments do you worry that most of these immunotherapies will be beyond the financial reach of all but the very rich?
Yes, I do actually. But I should point out there are other drugs, particularly some of the drugs that target the vasculature, that cost $50,000 per year and are basically given continually after initial treatment. And they really aren’t that effective. With these checkpoint blockade drugs [this type of immunotherapy] there is a pretty high quality of life and patients can quickly return to the workplace. The economic benefit to society with these drugs exceeds the costs. There are still some adverse events with these drugs but it’s nothing like that with chemotherapy.
Having said that, these drugs are too expensive. I do worry about the cost being too high. I think it’s not going to be possible if you give a combination of two of these drugs to charge twice the amount. That’s not possible and it will break the bank. I do think the price needs to come down and that it will come down with more competition with these drugs as more companies develop these treatments.
What drew you to science and cancer research in particular?
What drew me to science was just being curious as a kid. I liked to solve problems and figure out how things work. I had a chemistry set in the garage and my father supported my interests. I think he wanted me to be a physician but I was more interested in science. I was inspired by good teachers and I was lucky enough to be in a summer program after my junior year of high school at the University of Texas at Austin. There I got to do an experiment. It was kind of a silly thing – identifying how much iron a particular strain of yeast needed to grow optimally but it hooked me on science and lab work.
Cancer I became particularly interested in because my mother died from lymphoma when I was kid. I saw the effects of the radiation treatment she was receiving. I also saw the ravages of the treatment on her brothers who also died from cancer. One of her brothers had lung cancer and another had melanoma. I saw personally the toll that the disease takes. More recently my older brother died from metastatic prostate cancer. Both me and my other brother had prostate cancer, too, but we caught it quickly with me and I’m fine. It’s had a big impact on my family.
I didn’t specifically go into cancer research. I wanted to see how the immune system works. I worked on the problem because I was interested in T cells. It’s important to not just use your knowledge for the joy of learning and knowing something but to help people, too.
What sort of advice do you like to give to young scientists?
Science is fun but it’s hard work. I think there’s too much pressure now to tell people to work on translational science and do things that have immediate clinical relevance. I think what people should do is ask important questions in fundamental biology and every now and then think about how this impacts human health rather than spend all your time trying to solve a health issue. I think there is still a place for really good fundamental research.
What excites you going forward?
We know we can get durable responses lasting a decade or more with a few cancers. I’m optimistic as a field that we can eliminate or at least combat many types of cancer very soon.
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