We know immunotherapy works, but we need to find out why it doesn't, too

Interview/ Dr James P. Allison, American immunologist and Nobel Prize winner


What changed for you after the Nobel?

After the Nobel, several things changed for me. There came a sudden, not necessarily wanted, notoriety [laughs]. I couldn't go to a grocery store without people seeing me. I couldn't just be a person, you know. For a couple of months, my ability to work was affected because people would come up and see me. But it did all come back to normal, eventually.

My decision to go to cancer was based, I suppose, on my family history. My mother died from lymphoma when I was ten.
There is accumulating data suggesting a really tight relationship between the nervous and immune system... suggesting there may be ways to treat what we previously considered purely neurological diseases [with immunotherapy]

The positive thing that really happened was the fact that immunotherapy, which was so controversial for so many years—for long, it was considered 'voodoo', 'quack medicine'—[got recognised]. I didn't really get into the big argument for a long time, because to me it made sense to focus on my work and see how it really came out. We know now that it works. We know that a lot of people with cancer are getting cured now, and so, having it finally accepted as a way of treating cancers, that is really a positive thing. Now, I can actually sit down and have discussions with people who were like ‘you have to identify the causes of cancer and block the mutations instead of saying that we make the immune system work’.

Besides the Nobel, the thing that really consolidated the whole result (of Allison's work on immunotherapy) was that the American Cancer Society released data saying that the mortality rate due to melanoma had fallen by 18 per cent, and this has largely been due to immunotherapy. It has made a difference in people's lives, and as a scientist, as someone who mostly wants to figure out how things work, being able to do something that helps people... that has been really great.

It has worked for other cancers beyond melanoma, too.

Yes, the checkpoint blockade—CTLA-4 or PD-1 (that came afterwards; they keep the body’s immune response in check)—have been approved now for several cancers besides melanoma, including lung cancer, head and neck cancers, kidney and bladder cancer, cancers of lymphoma, and on and on…. There are about 30 different kinds of cancers. The response rates are 25-40 per cent… so we have got a lot of work to do. We know it works, but we need to find out why it doesn't, too. We are still doing our lab work on that, trying to see what's missing in the cancers that don't respond better [to immunotherapy]… what makes it different from people who respond better…. The goal now is to get us close to 100 per cent [smiles].

The good news in melanoma is that it is close to 60 per cent now; 55 per cent or so with a combination of CTLA-4 and PD-1 together. The five years of survival so far in a trial stands at 55 per cent. There is no reason why that wouldn't continue for ten years. If we just work hard, I don't see why we cannot get it over 55 per cent.

For a therapy that has offered tremendous hope for cancer patients, how has the response from them been?

There have been so many stories... so many letters that I have gotten from people, saying 'thank you, my wife was dying and was in hospice… and she got these drugs, and now, five years later, she's fine'. The most touching story is of Sharon Belvin, the first patient I met. In 2004, she was 22… and dying from metastatic melanoma. She had 31 metastases in her lungs, she had subcutaneous things on her skin, a half centimetre tumour in her brain. Sharon had failed every other therapy. But after she enrolled in one of the early trials, the tumour just went away! I hadn't seen her, but one day, her physician called and asked me to come down to his office. I said, ‘Why, I am busy.’ But he said, ‘No, no... come.’ He was with Sharon and her husband. Here was a woman who had been diagnosed with this disease when she had finished college, had just got married and started on with her life. Now, she has two kids. She has been in therapy for 16 years now. But her recovery was remarkable: the pathologist who was looking at her CT-scans was really amazed. He said, ‘Has there been some kind of mix up? Is this the wrong patient?’…. Over the years, I have seen [Sharon’s] kids grow up…. We have become friends now. It has been great.

Collaborators for life: Allison with wife, Dr Padmanee Sharma | AFP Collaborators for life: Allison with wife, Dr Padmanee Sharma | AFP

What would you recall as your most challenging experience in the journey?

The question about the most challenging experience is an interesting one because science presents you with challenges all the time. You have to figure something out and know that you are right. If you have a sound belief that there are such things as facts, which is not necessarily universally felt these days, you could test them and come up with these ideas…. My work was designed to figure out how the immune system worked, not to discover a cure for cancer. But when we found this negative checkpoint, I had the idea that [if] we blocked it, that could cure cancer. We did the experiments and we could cure almost anything in mice….

At that point, I wanted to, obviously, bring it to patients. But for three years or more, I had no luck. I was working at the University of California, Berkeley, in a basic science lab; I had no industry contacts. So I had to go out and try to find some company that would buy my idea, but they wouldn't do it. I ran into so many things that were just ridiculous. People said ‘immunotherapy has never worked, it will never work’. Or, ‘okay so you cured cancer in mice, anybody could cure cancer in mice’. First of all, that's not true! It is not a trivial achievement. Even in mice. My response as a scientist was always that how are you going to know if you don't try it. Let's do the experiment. If the massive data I have isn't sufficient to actually try a clinical trial, then, I mean, you are a moron [laughs]. I am a scientist, I have data and I could show you this; if you don't buy it, you don't do it. But the reasons that were given to me were not scientific, they were biases.

Finally, we met with a company that wanted to make the antibodies, and we teamed up with them. They made this antibody that got approved by the Food and Drug Administration. It is called ipilimumab, or 'ippi'… kind of like a chewing gum, I don't know why they named it that [laughs]. In 2010, they completed a clinical trial that showed that little over 20 per cent of patients with melanoma were alive for almost five years with this treatment. No drug of any type had extended survival with melanoma. When we started this work, a diagnosis of metastatic melanoma meant a life expectancy of seven months, and almost nobody lived past five years. And here we had 20 per cent! It was disappointing [in a way], you know, why not a 100 per cent? That is what is we are working on now…. We need to make it work for everybody, that's my goal.

What works in animals often fails in humans. What convinced you that this would work?

I was sure it was worth taking a chance. You are correct in that everything that works in mice won't necessarily work in humans. But I had never seen data as strong as ours. It was not just in one kind of cancer or in one strain of mice. We tried with several different cancers and many different strains of mice, and it always worked. I was sure enough that it had a good chance to work. So I made my decision, and… I was betting the rest of my career on that, to just do whatever I had to do, to get people in the clinic and see if it worked on them, too. I couldn't stand, as a scientist, people saying that nothing like that has ever worked before. That's not science, that's just bias. How would we make progress if that's how we thought. We knew the prevailing attitude was wrong, and the only way to prove it was to challenge it.

Tuned in: Allison plays the harmonica during a performance with The CheckPoints, the house band of the Society for Immunotherapy of Cancer, at the Cancer Research Institute 2018 Awards Gala at Metropolitan Club in New York City Tuned in: Allison plays the harmonica during a performance with The CheckPoints, the house band of the Society for Immunotherapy of Cancer, at the Cancer Research Institute 2018 Awards Gala at Metropolitan Club in New York City

Within immunotherapy, what made you choose cancer?

My decision to go to cancer was based, I suppose, on my family history. My mother died from lymphoma when I was ten. She had radiation therapy and that ravaged her. I was holding her hand when she passed away. That made a real impact on me. Two of her brothers also died—one from melanoma, and another from lung cancer. I think I just had it in the back of my mind if I could understand the immune system properly, then maybe I could really make a well-educated decision about how to go after cancer. I had read a lot of stuff about what people were doing and most of it was not based on solid science. Rather it was based on suppositions and assumptions that were wrong.

I had dabbled in immunotherapy over the years occasionally, but then when we got CTLA-4, a lot of data that we had just came together in my head. We began doing this work with the mouse experiments. Jeff Bluestone was the other person who simultaneously discovered CTLA-4. After it was published, it was in the textbooks that it was not a negative [checkpoint], [but] a positive regulatory thing. And both of us said that that was wrong…. Jeff decided to take this work because he is interested in autoimmunity and diabetes. He went down that track. My family history took me to cancer.

What are your thoughts about the potential of immunotherapy in areas other than cancer?

I think the success [of immunotherapy] in cancer is leading to other applications as well. One of the things that we do is block the negative, but if we could somehow deliver the negative signals, you could treat autoimmune diseases, diabetes, multiple sclerosis and other nasty, debilitating diseases. There is accumulating data suggesting a really tight relationship between the nervous and immune system... suggesting that there may be ways to treat what we previously considered purely neurological diseases [with immunotherapy]…. So I have got someone in my lab who is now working on [understanding the connection with the immune system]. I think that it has led to answers to a lot of applications, a lot of understanding of how all the systems are really integrated.

How hopeful are you of its use in these conditions?

I do have hope. I think it is going to take time. You cannot just jump into it…. You got to see what the immune system is doing, understand the fundamental aspects of the science, before you can think about how to integrate, or maybe try. That is why immunotherapy in cancer didn't work for so long. You got to know the details, really study and understand exactly what's going on, before you could be at the right place at the right time.

What are your current projects?

Most of what we are doing now is cancer. It is what I call reverse translation. So we studied what happened in the mice and took it to the humans. Now if you want to understand it better, you got to study what is going on in the humans, generate hypothesis and take it back to the mice. Dr Padmanee Sharma, my wife and collaborator, [and I] run a lab, where we are involved in over a 100 clinical trials, where we get specimens from patients undergoing these therapies and analyse them [right down to the] molecular level to see what is going on. Our philosophy is that we should learn from every patient in the trial. If the therapies don't work on them, then we need to figure out why…. There are a lot of technologies that have come up in the last couple of years, enabling us to look at the genes that are expressed, the cells that are there and really build up a picture. We know what a successful response looks like now. So if it doesn't work all the way, we can identify what's missing. For instance, there are certain types of macrophages that can turn off T-cells, and so, we are working on ways of either eliminating them or turning them into other macrophages that won't inhibit T-cells, so that we can get a better response.

Dr Sharma has a trial where we have learnt some things from the biopsies of prostate cancer patients.... Every company had given up on prostate cancers [because of not being able to find an] immunologically responsive target. We figured out why that was, put together a combination [to test in a] large trial to see if it works. Hopefully it will, we don't know yet.... That's what trials are about.

The major companies shut down their work [on prostate cancer and immunotherapy]; they said that it won't work. We made some observations and showed them the data [and made some suggestions]. So, we did the trial and it worked somewhat, it didn't work in some ways. Now we are refining it, and we will see.

Cancer is tough. But some cancers are more difficult than others.

Oh yeah... unfortunately glioblastoma and pancreatic cancers are still pretty much resistant…. They take too many people. They are rapidly lethal. But we are studying biopsies, we are getting some ideas. Actually a lot of labs are studying... There are some studies with a combination of five different things... too early to say if they are curative. They seem to be slowing the diseases.... With other types of cancer like bladder and kidney, we get 30-40 per cent response rates, we need to get them higher. But then there are these other ones where we are nowhere, [and] need to get above zero. I am optimistic because we could begin to identify the barriers preventing immunotherapy from working. Now, it may take the help of chemotherapy, radiation, multiple modalities, where the idea is to kill some tumour cells and let the immune system take on from there.

In what way is immunotherapy a paradigm shift in the range of options that are currently available to treat cancer?

Earlier, surgery was the first pillar of cancer therapy, then came radiation with Madame Curie, then came chemo after World War II, and now immunotherapy.... But unlike the other three, immunotherapy can work with all of them because when you kill cancer cells, that will provoke immune responses, but mechanisms… will stop it before it can become effective enough. So if you got cancer… and may be you think… I don't have to kill every last cancer cell with chemotherapy, with radiation and shut down the immune system. All I need to do is kill enough tumour cells, and then let the immune system come in. It will require radical rethinking. People keep asking me, ‘is this the end of radiation, chemotherapy? Are we done with them?’ I say no, we are not, but that we are done with them as sole agents, because it is too hard to cure people with them most of the time. With a few cancers they work, but with a large majority, they don't work by themselves. We can use them with immunotherapy to have a synergistic effect, drop the exposure to radiation and chemo to a point where it is less toxic, your hair doesn't fall out, your immune system isn't destroyed, you are not susceptible to infections. It is going to take a while to figure out the balance; that's the other thing we are working on.

What about Indian researchers? Do you think access to immunotherapy for cancer patients is an issue?

I have had a number of Indian researchers in my lab, some of whom have gone back to India and done great work. They have been a rich source of intellectual vigour…. [I understand that] perhaps, support for science is not quite enough [there] and there might be a lot of reasons for that which are understandable, given other needs of the country. As far as access to drugs goes, without getting into too much details, I would say that they are highly overpriced, and ought to be given to people at a reasonable price. But that is a separate issue…. In terms of science, there is quite a lot of activity [among Indians], including those going back and people coming here. India is a valuable contributor.

You exude a lot of hope when it comes to something as difficult as cancer. But a section of experts feel there is a lot of hype when it comes to treatment modalities in cancer.

I understand the pessimism. It is really difficult to use the word 'cure' and 'cancer' without provoking doubt and suspicion. Not everybody can have a single round of treatment and be alive 20 years later. About 20 per cent are alive over a decade and so I think that qualifies as cured. There are hundreds of different cancer diseases—not one kind, one tissue, not one cause, but many different causes…. So, I don't think we will ever make cancer disappear, but we can do it a step at a time. We can reduce mortality from melanoma, which has already been done. And it will be soon so for lung, bladder and kidney cancers. We just need to keep working at it. We will never be able to totally defeat it…. But I have the optimism because I know that we are beginning to learn basic rules. We couldn't say that ten years ago; nobody could say I know how to cure any cancer, except maybe testicular and some kinds of leukaemia, but majority of cancers had no hope. Now we know there is. The message I would like to send out to everybody is that a cancer diagnosis is not necessarily a death sentence. We just got to work harder on it.

Through this time, is it your music that has kept you going?

[Smiles] That helps. I have been part of a couple of bands. Though lately, we haven’t been playing because of Covid-19. Besides, I love science, figuring things out. I like the fact that what I do, to some extent, helps people and that's important to me, too. It is important that what we do makes the world a better place, through science, through music, hopefully both.

A few years ago, a physician told me that while he was curing one patient at a time, as a scientist, my work was curing hundreds of thousands at a time. There is a lot of work still to be done on different checkpoints. But we are looking at other things, too. Oncolytic viruses [for treating cancer], for example. Putting genes into viruses to help tumour cells express things, and attract the immune system better…. There is a lot of exciting work being done in immunotherapy.

Do you still play music at home?

Yeah some, not much. Now that you bring it up, I think I should play a little bit more [laughs].