Robert Schreiber: "We are getting closer to turning some types of cancer into a chronic disease"

It is a good time to be an immunologist, says researcher Robert Schreiber (New York, 76 years old), professor of Pathology and Immunology at the Washington University School of Medicine.

“It is an exciting time: we are in the golden age of immunology and cancer immunotherapy”, he says with a smile from the imposing Ramón Cajal classroom at the University of Barcelona, ​​where he is about to be awarded an

for his scientific contribution to the demonstration that the immune system can be a therapeutic tool against cancer.

These are good times for research in immunology, but this was not always the case.

“When young people say to me: 'But wasn't this [that the immune system can help fight cancer] already known?'

I tell them, 'Let me tell you a story…'” laughs Schreiber.

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Immunotherapy: the vanguard against cancer

It was not an easy road to put the immune system at the center of the fight against cancer.

Its potential role in fighting tumors was an old idea, from the beginning of the 20th century, that hadn't quite caught on;

and it remained there, as a mere hypothesis, stranded in the minds of some researchers who “then did not have the experimental impulse to specify what was happening”, admits Schreiber.

But years later, he and his team took up that idea again, which, based on small findings, culminated in the demonstration, in the early 2000s, of the rules of the game between the immune system and cancer: Schreiber postulated the theory of immunoediting of cancer, the paradox that, although the immune system protects against tumor cells, it can also promote their development.

His findings helped open the door to immunotherapy against tumors, the great therapeutic revolution of the last decade.

Ask.

If the immune system can protect against cancer, but can also favor its development, is it our friend or our enemy?

Response.

We're still trying to figure that out, actually.

It's a process: the first part is that if the immune system recognizes a tumor that has formed because there are abnormal proteins, it can destroy those [malignant] cells;

but if the tumor is heterogeneous—and many are—it has cells that don't express that mutation and the immune system doesn't recognize them, so by removing only those that can be easily recognized, it leaves behind a troop of very bad tumor cells and they grow.

P.

New cancer treatments emerge, they work, but then tumors always appear that generate resistance.

It is like an eternal race between cat and mouse.

R.

This is why very few of us will use the word cure when we talk about the response to cancer.

It's a cat-and-mouse game, yes, and it starts naturally, right when cancers arise: the immune system can see some of those cells and get rid of them.

And what are we left with if they start to grow again?

There are now great immunotherapy drugs that show remarkable effects in perhaps 20% of patients.

If it is melanoma, in 80%, but in many of these tumors only 20% respond.

So you go with another treatment, even radiation.

Radiation can produce new mutations in a tumor and give the immune system another chance to kill and get rid of tumor cells.

But others will come.

And we don't know if it will be years and years of treatment with different combinations of therapies.

Many believe that what is possible now is to make cancer a chronic disease, like diabetes: you would die if you were not treated with insulin, but if you take it, you can live for many years.

We believe that this is the possibility offered by immunotherapy against cancer.

P.

What happens in tumors such as breast or pancreas, where immunotherapy does not work?

What differentiates these neoplasms from those of the lung or melanoma, where it does work better?

A.

We are trying to resolve this question.

Some people consider that it is simply because of the number of mutations that a particular cancer has: melanoma has many mutations, it can give a thousand, and pancreatic melanoma, much less.

But we consider that tumors are little universes unto themselves and contain not only tumor cells, but many other cells.

The pancreas has a very high level of myeloid cells and produces a desmoplastic [fibrous] environment: the tumors are like small rocks and the T cells [the lymphocytes of the immune system] that would be eliminating the cancer, have great difficulty entering there;

and when they go in, they run into these immunosuppressive myeloid cells and that makes it even worse.

Q.

Will immunotherapy end up relegating other treatments, such as chemotherapy or radiotherapy?

A.

Chemo and radiotherapy work very differently from immunotherapy, although there is a feeling that even in those types of non-immunological therapies, there is an immune component: when you treat with radiation, you create new antigens and the immune system, then, he sees them and they can facilitate destruction.

We think ultimately you're going to need to have the ability to do different combinations and we need the guidelines, like figuring out what the criteria are for using radiation therapy plus immunotherapy, immunotherapy alone, and so on.

Schreiber poses in the arcades of the rectorate of the University of Barcelona, ​​on June 1. Gianluca Battista

Q.

What do you still need to know about how immunotherapy works?

A.

Compared to where we were 20 years ago, we know a lot more now than we did then.

But we still have a lot to learn about how the immune system works and how we can attack certain things to make it work better or to block something that suppresses it.

The great challenge is to translate these findings that we often get from experimental animals to humans and see how they work and how we logically choose the types of therapy with which we would treat a patient.

We are in a revolution, we have several things that are working a little bit, but we have to figure out how to make them work consistently in all patients.

The type of vaccine that pharmaceutical companies will be most excited about will be the one that targets common mutations in tumors.”

Robert Schreiber, immunologist

Q.

How is the research on cancer vaccines?

A.

We were one of the first laboratories to demonstrate that, if a tumor is sequenced, mutations are identified and it is predicted which of these mutations are good antigens for T cells, a vaccine could be made, vaccinating an animal carrying tumors and have them reject your tumor.

And that has been brought to the clinic and there are various groups around the world that are trying to do this.

But we showed this with vaccines that were made with peptides that included the mutation we were targeting and there were 10 to 20 in the patient: the problem was that these were highly personalized vaccines, so the only person in the world who would benefit from this vaccine would be that person we sequenced.

And Big Pharma hates this idea because they don't like personalized.

They want widespread [drugs].

An idea that haunts us, now that there are more groups working on this and sequencing, is that we are finding mutations that are seen in more than one patient.

Steve Rosenberg's group, for example, discovered that the KRAS gene is mutated in 20% of human tumors and may be an antigen that could be used in a vaccine for many people.

I think the one type of vaccine that drug companies will be most excited about will be vaccines that target common mutations in tumors.

P.

Being realistic, will we be able to see cancer disappear or rather see it become a chronic disease?

A.

My feeling is that I think we're about to see cancer as a chronic disease, although we lump everything into the big term cancer, and there are so many differences… But certainly I would say that for some types of cancer, we're getting closer. getting closer to becoming a chronic disease.

Every once in a while, you see these patients whose cancers never come back and it's fantastic, but I think we have a lot more to learn before we can say we can cure it.

This is why we are so careful about using the word cure.

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