“Brain tumors will be treated with CAR-T therapy”

Over the past twelve years, more than 35,000 people with cancer have been cured using CAR-T cells. The treatment involves extracting immune cells from the patient’s blood, modifying them to attack cancer cells, multiplying them to produce an army of immune cells, and transfusing them back into the patient.

CAR-T therapies would not exist if it were not for Carl June, an immunologist at the University of Pennsylvania in the US, who played a key role in their development and first demonstrated their effectiveness by saving the girl Emily Whitehead in 2012. six years old, suffering from leukemia, for whom there was no other choice. For this achievement, Carl June received the Abarca Prize in Madrid, which is awarded by the HM Hospitales Foundation to researchers “whose work has made a transcendent contribution to improving the health of individuals and populations.”

CAR-T therapy is approved to treat several types of leukemia, lymphoma and multiple myeloma. What other types of cancer do you think could be cured with CAR-T?

I think that eventually all cancers will be treatable with CAR-T. In the laboratory, we saw that almost any type of tumor in mice could be treated with this therapy. To do the same in humans, we need to develop the next generation of CAR-T that is even more effective, as well as study the combination of CAR-T with other treatments. I am optimistic that we will see important progress in this direction in the coming years.

What new type of cancer do you think will be the first to be treated with CAR-T?

Brain tumors. Three research groups have begun trials in patients. One at City of Hope Hospital in Los Angeles, the other at Massachusetts General Hospital in collaboration with Harvard University and us at the University of Pennsylvania. The results are very promising. The treatment was safe and we have evidence of effectiveness in all three studies. This is the first phase of testing and there is still work to be done. But the fact that three independent groups reported benefit makes me very optimistic that within five years we will have CAR-T cell therapy for glioblastoma (the most common brain tumor with the worst prognosis). If we had done it ourselves, I wouldn’t be so optimistic.

But so far it hasn’t worked. What has changed?

In two previous studies, we inoculated CAR-T cells into the blood of glioblastoma patients. Now we’ve grafted them directly into the brain. This is the main difference.

He states that he is “very optimistic that within five years we will have CAR-T cell therapy for glioblastoma.”

Can CAR-T cells successfully treat pancreatic cancer?

It will take longer and require a lot more research. In my laboratory, we are exploring a strategy to combine CAR-T cells with oncolytic viruses produced in Barcelona by Ramon Alemany (of the Idibella Institute and Theriva Biologics). We started working in this direction when Sonia Gedan (who completed her PhD with Ramon Alemany and now works at the Idibaps Clinical Hospital Institute) came to my laboratory. We have some very interesting results that we are going to present soon. I think this is the most promising strategy for treating pancreatic cancer with CAR-T cells at the moment.

CAR-T cells have begun to be tested for the treatment of autoimmune diseases. What potential do you see in this?

This is a very amazing new concept. All previous treatments for autoimmune diseases (in which the immune system attacks the body’s own cells) were based on immunosuppression. CAR-T cells seek to reboot the immune system, much like rebooting a computer. Researchers in Germany provided data from fifteen patients with three different autoimmune diseases, and 100% of them responded. Currently, more than eighty clinical trials of CAR-T therapy for autoimmune diseases are being conducted around the world. This is an exciting moment.

I think eventually all cancers will be treatable with CAR-T.”

Which autoimmune diseases are prime candidates for treatment with CAR-T?

Lupus is the most studied disease. The German team also studied it in patients with myositis and systemic sclerosis. Trials for multiple sclerosis are being conducted in the US and Europe. Good results are observed in various diseases.

Could it be a cure for type 1 diabetes if diagnosed before the immune system destroys insulin-producing cells?

California-based Sonoma Biotherapeutics is trying to do just that. They do this using regulatory T cells (which regulate the immune system and are different from the cytotoxic T cells used to treat cancer with CAR-T). He hasn’t reported the results yet, but I think it’s promising. Another possibility for the future is to administer insulin-producing cells to people with diabetes, followed by CAR-T regulatory cells to prevent them from being destroyed by the immune system.

Will this mean a cure for type 1 diabetes?

This is the idea. It is effective not only for early diagnosis, but also in cases of advanced disease. I think we’ll see that. I hope we can cure type 1 diabetes within five to ten years.

“There are more than 80 clinical trials of CAR-T in autoimmune diseases being conducted worldwide”

Could immunotherapy be useful for other diseases that involve the immune system?

I think so. At the University of Pennsylvania, we just published two studies that treated the effects of heart attacks with immune therapy. We’ve done this in mice, but not yet in humans. We started a company to test it in patients with cardiac fibrosis.

What about neurological diseases such as Alzheimer’s disease, which also have an immune component?

Many forms of dementia are associated with neuroinflammation. In the future, they may be treated with immune therapy. But we are at the beginning of the journey. The first diseases to be treated with CAR-T therapy after cancer will be autoimmune diseases.

Do you think side effects will limit the use of CAR-T therapy?

What is acceptable as a side effect for a fatal disease is very different from what is acceptable for a less serious illness. Initially, one third of people treated with CAR-T cells suffered from cytokine storm (a life-threatening overactivation of the immune system). Now there are less than 5%. We have learned to prevent and better manage the side effects of treatment.

“We hope to be able to cure type 1 diabetes within five to 10 years.”

Are you concerned that CAR-T cells not only treat cancer, but can also cause it?

This came to light last November when it was reported that a small number of patients treated with CAR-T subsequently developed hematological cancers. It has been known for many years that people who have had lymphoma have a higher risk of developing another lymphoma than the average population. But those treated with CAR-T do not appear to be at higher risk than lymphoma patients who were not treated with CAR-T.

What message would you give to a patient concerned about the side effects of treatment?

About peace. At my hospital, we reviewed the cases of 780 patients we treated with CAR-T. We have not had a single case of T-cell cancer development. For a person with cancer, nothing has changed in terms of the appropriateness of treatment.

“I think it’s a brilliant idea,” he says of the Caixa Research Institute project in Barcelona.

Trials have begun on CAR-T cells produced in patients’ own bodies rather than in a laboratory. What advantages does it have?

It is being tested, no results yet. The idea is to modify immune cells in vivo, for example with messenger RNA, rather than ex vivo in the laboratory. The advantage is that the therapy can be mass-produced, which should reduce cost by not having to individualize it for each patient. It is also a less aggressive therapy than using ex vivo-derived CAR-T cells. We don’t know how long the modified cells will remain in the body in vivo, but in autoimmune diseases we probably won’t need them for long. I think these two options will coexist because one or the other may be better depending on the disease we want to treat. For autoimmune diseases, in vivo may be better, and for cancer, ex vivo.

Will the cost of CAR-T cells be a barrier to reaching all the patients who need them?

The cost will decrease for several reasons. Firstly, because the most important cost is human labor, and some of this work will be automated. Because right now all CAR-T treatments are developed individually for each patient, but in the future some of them may be mass-produced and use the same CAR-T cells for different patients. And another way to reduce costs is what they did in Barcelona. Manel Juan (from Hospital Clínic) joined my laboratory in 2013 to study CAR-T cell technology and develop treatments in academic and clinical settings.

He seems to be well aware of what’s going on in Barcelona. What do you think of the CaixaResarch Institute project, which will research immunology with the prospect of applying advances in areas such as cancer, infections and neurological diseases?

I don’t know the project, but it seems like a brilliant idea. We have learned that the immune system is the cause of many diseases, such as cardiovascular diseases caused by inflammation, neurodegenerative diseases, autoimmune diseases… A better understanding of immunology will be useful for many areas of medicine.

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Joseph Corbella