James Allison was 10 years old when his mother died of cancer. Shortly after, the same disease took two of his uncles. More recently, his brother died of a prostate tumor. A few months later, Allison himself was diagnosed with the same tumor. He had surgery and recovered. Another appeared in his bladder, and he received successful treatment. Then a melanoma appeared on Allison’s nose, followed by another tumor on the back of his head. Fortunately, all were detected in time, and he was cured. Suffering and overcoming four apparently unrelated cancers is an extraordinary feat. And Allison, a researcher at the MD Anderson Cancer Center in Houston, also happens to have invented the most effective cancer therapy in recent decades: immunotherapy.
The first cancer patient treated with immunotherapy was Sharon Belvin, whom Allison met in 2004. The 24-year-old had advanced skin cancer, which at the time meant certain death within six or seven months. Eighteen years later, she has had two children, and she lives cancer-free. “I see she’s quite regular,” Allison says. It is not an isolated case: the therapy, he says, has allowed hundreds of thousands of people to overcome melanomas and other tumors.
The drug Belvin received is called Ipilimumab. Its formulation began with a discovery Allison had made years earlier. This 73-year-old Texan is more of a scientist than a doctor. His specialty has always been the study of T lymphocytes, a type of white blood cell capable of locating and annihilating foreign intruders in the body.
“These cells go through your body, through the tissues and the blood, and defend you,” Allison says. He recalls a conversation with a chemistry professor during his time at the Universty of Texas at Austin in 1969. “I went to see him in his office and said, How does that work? He said, Nobody has a clue. I thought, Well, I’m going to figure this out,” he recalls.
He dedicated his life to answering that question. In the 1980s, his research team discovered TCR, a molecule that Allison likens to a car’s ignition key:for a lymphocyte to attack an enemy, it must be activated, but that’s not all. In the early 1990s, his colleague Fiona Harding discovered CD28, another molecule that functions like a car’s gas pedal. But something was still missing for the researchers to be able to control lymphocytes at will. Finally, in 1996 Allison and his colleagues at the University of California at Berkeley discovered a third molecule, CTLA-4, which they compare to a brake pedal. The molecule prevents lymphocytes from recognizing and destroying tumors. The drug Ipilimumab —approved in 2011— deactivates that brake, launching white blood cells against the tumor. The patient’s immune system, not the drug, ends up eliminating the cancer.
The Japanese cancer researcher Tasuku Honjo also discovered another of these brakes, PD-1, and developed another similar immunotherapy, based on immune checkpoint inhibitors. Allison and Honjo won the Nobel Prize for Medicine in 2018 for their work. According to Allison, the award marked the first time that the academy gave the prize to a cancer therapy and not to basic discoveries about the disease. That year, Allison also won the Frontiers of Knowledge award from the BBVA Foundation.
The researcher now directs a new research center, which bears his own name, at MD Anderson. He works alongside his wife, Padmanee Sharma, an oncologist, immunotherapy pioneer and bladder cancer specialist. Sharma forced him to get tested for bladder cancer when he first discovered blood in the toilet, and she helped to diagnose and remove the cancer quickly.
Current immunotherapy works well in some cases—in more than 50% of melanoma patients—but little or not at all in others. Allison is currently working to find new immunotherapies that work in more patients, particularly for the most deadly cancers, such as brain glioblastoma or pancreatic cancer, which have not successfully been treated by immunotherapy.
Outside of his rigorous work, the friendly white-haired immunologist is passionate about music. He acknowledges that he made his choices about where to base his research based on the music scene of the destination cities. He plays the harmonica in a blues band made up of other scientists, which has performed at many cancer research conferences, and has shared the stage with idols like Buddy Guy and Willie Nelson. His motto is “work hard, play hard.” In this video interview, the Nobel laureate in Medicine explains about new immunotherapies he is looking for and what the cancer treatments of the future will look like.
Question. Your life has been marked by cancer since childhood. What would you say to people receiving a diagnosis?
Answer. My mother died of cancer when I was about ten, actually had died of cancer. And then I just thought,someday I hope I can do something about this. It drove me all the time, but it was sort of in my head. I actually had hoped that I’d get the CTLA-4 immunotherapy, which was in clinical trials, done in time for my brother, but I did not. Should I have a recurrence, these treatments are there now. It’s very important for people to realize that the diagnosis of cancer is not necessarily death anymore, even for the ones that ten years ago meant almost certain death, such as metastatic melanoma. The median survival after diagnosis was seven months, and fewer than 3% of people were alive five years later. Now, with a combination of Ipilimumab and PD-1, almost 60% of metastatic melanoma patients are alive six years later. Those people are cured. They don’t have to look over their shoulders anymore and worry about it. But we’re not there in other cancers yet. We need to keep working.
Q. Do you think that one day we will understand the immune system so well that we will be able to stimulate it so that it completely eliminates all cancerous tumors?
A. That’s my goal. I doubt if we’ll be able to get there in all kinds of cancer. We’ve got a chance with some cancers. With melanoma we can get up to 90%. With bladder, kidney, lung, we’re at 40%. We’re learning more almost every day about what’s going on, and we know we needed to start using combinations of drugs to get melanoma close to 100%. For bladder and kidney, those combinations let us eliminate up to 50%. Then we have glioblastoma and pancreatic cancer, two really lethal tumors that we really don’t have much insight about, but we are gaining information.
Q. Has there been any progress with those tumors?
A. When CTLA-4-based immunotherapy was not yet approved, my wife began taking tissue samples from bladder cancer patients receiving the treatment. Almost no one did that. We just looked at statistical improvement and median survival. Thanks to that work we have learned that this is not just about T-cells. People are shocked when I say this at scientific conferences [laughs]. There is another type of cell, called myeloids, that is very different from lymphocytes. You usually see them intervening in wound healing, but sometimes they also help eliminate infections. They are not as specific as lymphocytes, but they help clear the infection.
Brain and pancreas tumors are full of these cells, and we have seen that they inhibit the activity of T-cells. It is possible that they do so by expressing checkpoints differently from those we know. We have discovered at least one of these checkpoints, and we are studying it because we may be able to stop these cells from going to the tumor, which may allow the lymphocytes to fight the cancer. It is also possible that we can modify the activity of these myeloid cells and turn them in our favor. This opens up a whole new field of investigation.
Q. What is your current approach to finding new treatments?
A. The first thing is to learn the basic biology of all immune cells as quickly as possible. When we’re ready, we’ll start small clinical trials with about 12 selected patients. We treat them, we take biopsies of their cancers, we sequence all the RNA cell by cell, we sequence the entire genome of the tumor, we cut the tumors into slices and analyze each one of them to know what molecules are there, what type of cells are there and how they are interacting. That way we will be able to understand the role of a type of myeloid cells called macrophages, and we will see if they impede the work of lymphocytes against cancer. We need to do this with every patient after every treatment. For now we have a pillar, which is the use of the two immunotherapies mentioned, but we can get a third, fourth or fifth that manage to overcome the problem of resistance in tumors with a worse prognosis. I think we can make it.
Q. Why does immunotherapy work so well for some people and not for others?
A. One of the reasons is that the more mutations the cancer has, the better this treatment works. Melanoma, and tumors in the lung, head and neck, bladder, stomach, all tumors associated with tobacco smoke, for example, have many mutations. And lymphocytes are very effective for those: they manage to detect cells with a single change in their genome, a single mutation. The more mutations, the more lymphocytes will be activated against the tumor.
Q. Does the microbiome—gut bacteria—influence the success of immunotherapy?
A. It’s been shown now very convincingly by my colleague Jennifer Wargo that in melanoma patients, the kind of bacteria in your gut makes a difference. A high fiber diet is associated with better responses. You ought to be eating a high fiber diet anyway. Some people think that we may be able to find good bacteria and replace bad bacteria with the good ones. It’s a little too early to know about, but it certainly plays a role. In some kinds of cancer, there are actually bacteria surrounding the cancer that are more directly influencing things. Bacteria have receptors called Toll-like receptors that are like a primitive immune system. When they are attached to the tumor, their presence can generate an immune system response. We’re still trying to figure out what that’s all about, but it’s important.
Q. What will future cancer treatments look like? Will we have vaccines?
A. A lot of people ask me if chemotherapy is going to go away. The answer is no. It is very effective against some types of cancer. The problem is that chemotherapy and radiotherapy very rarely manage to cure the cancer, to eliminate all the cancer cells. What they do is initiate an immune response. Lymphocytes are activated when they see dead cancer cells because they cause inflammation. The problem is that current treatments do try to eliminate every last tumor cell with radio or chemo. And this is a problem because many lymphocytes are also killed this way. We have to change the way we give these two treatments, not expect to kill all the tumor cells with them. The idea is to use some kind of vaccine to stimulate the immune system and let it finish the job.
Regarding these vaccines, I think they will first be therapeutic. We will give them to people who already have cancer. Now it is possible to sequence the entire tumor, determine all its mutations and perhaps make a cocktail of molecules for the immune system to destroy that tumor. Much later are preventive vaccines. There are some cancers that are caused by hereditary genetic factors, such as Lynch syndrome or those suffered by women who have the mutated BRCA gene [which generates proteins that prevent the formation of tumors]. If we manage to identify molecules that are expressed before the tumor appears, we may be able to achieve preventive vaccines. They will not be valid for all tumors, but perhaps for hereditary ones.
Q. You say that you have to learn from each patient, and you have criticized that sometimes it is impossible because some pharmaceutical companies do not publish the results of clinical trials in which a drug does not meet expectations. Do you think that the industry hinders the advancement of science in this field?
A. Pharma becomes the bad guys in a lot of stories. Every single person that I know in pharma desperately wants to help cancer patients. It’s just that sometimes the rules lock them in. The FDA requires trials of a certain type. The most frequent objective is to increase patient survival. But it shouldn’t always be because sometimes you stay very close to the target. You may have something very beneficial on your hands, but all the data from that trial remains unpublished because the primary objective has not been achieved statistically. In these cases there should be at least one collection of data at the molecular level from a few patients. We should make sure we have a mechanism that we think is going to get us most of the way there, and then turn it over to somebody to do a big trial to look for survival benefit.
Q. Immunotherapy is the fourth pillar of cancer treatment after surgery, chemotherapy and radiotherapy. What will be the fifth?
A. The fifth pillar is going to be combining the ones that we have. Right now it’s too patchy. They need to be brought together, but they need to be brought together based on mechanisms, not just because one company owns two drugs.
P. Do you think that the personalization of cancer treatments will generate more inequality between patients who can afford it and those who cannot?
R. Some time ago I was at a conference in Taiwan. They nationalized their health system, and they have to ask how much benefit for the dollar are we going to get herewith the treatments. The combinations are very expensive. The two current immunotherapies cost about 220,000 dollars [about 209,000 euros] per patient. That has led to some decisions that influence what’s available in countries with nationalized health insurance, which is a problem. In the US, if you don’t have insurance, it’s very difficult to get access to these things. In a lot of countries, they’re theoretically available, but they’re just financially beyond reach. I know the risk that pharma companies take in developing, on the other hand. They charge a little bit extra with their winners so they can take more chances. But you have to stop at some point. The cost for some drugs bears no relationship to the cost of making them anymore.
Q. Have you made a lot of money from immunotherapy?
A. I’ve made some money, of course, but it’s not lucrative, not like if you start a company and then you sell it. I only have one patent. The University of California got half of the proceeds. The other half was distributed among the people in my lab.
Q. What is the next big challenge for you?
A. We’re starting this institute here, which is actually named after me, to my surprise. Its goal is to do the sort of things I’ve been talking about, the mechanism-driven trials based on knowledge of fundamental properties and knowledge about how the immune system works. One of the new things is that we can take a single cell and analyze all the RNA that is in it. That gives you information on all the genes that are turned on. We normally define cells based on the molecules they produce. For example, all lymphocytes have a molecule called CD3. And if they are killer lymphocytes they also have the CDA molecule. Then there are others who have CD4. We have realized that these differences are a continuum. You cannot just put them in a box and classify each immune cell, because many fall between one type and another. And they also change depending on the environment they are in. We will be able to clarify what differentiates an activated killer lymphocyte from another that is inhibited and cannot act. We can even learn to train them, to modulate them. Increasing computational power will help us with that. Now it takes a week to analyze a single slice of tissue from a tumor and months to understand it. The complexity is a lot more than we thought.
Q. When you were in high school in your hometown of Alice, Texas, you skipped biology class to protest that Darwin’s theory of evolution wasn’t even mentioned in passing. Those responsible for the center did not change the classes, and you had to take the course by mail. Do you consider yourself a religious person?
A. It’s a question that has nothing to do with science. Science helps us understand the universe to the point where we can predict what will happen if we start a biomolecular reaction. That’s science. Evolution is a fact. The problem is that we don’t know the facts about how it all started. What was the origin of everything. I don’t think we can ever know. It comes down to a whole different realm, which is faith and belief. I am spiritual. I believe that there is something out there that was the origin of everything. I don’t identify with any religion, but I respect that others do. What I do not accept is that someone says that they do not vaccinate their child against covid because their religion does not allow it. It’s stupid and counterproductive. Every day I try to get up before the sun rises. For me that is the most splendid moment of the day, when the sky begins to brighten and the birds begin to sing. For me, God is something like that. It’s just a feeling, something personal. The rest of the time I try to do more research on cancer to help people.
Q. What do you mean by the second part of your motto “work hard, play hard”? Does it refer only to music?
A. No, it refers to enjoying life. It’s something I’ve always tried to do. For me, the people I work with in the laboratory are almost like my family, especially when we were younger. We finished work and we all went to the bar to party. Always together. Now we don’t do it as much, but I still try to convey the same message to my people. You have to enjoy the work. It has to be fun. If it’s an obligation, it doesn’t work. The ideal is when work is so much fun that you can’t differentiate it from the party, from pleasure. You always have to have fun, working, living and playing.