CAR T Cells

The therapy still costs up to 400,000 euros. But costs can be reduced by improved production methods. The new variant of CAR T immune cell therapy is now also targeting solid tumors. The modified immune cells can even track down metastases. This gives hope to many patients. Fraunhofer helps to put scientific excellence into practice.

Michael Hudecek is one of the pioneers of cellular immunotherapy, and co-developed the first wave of CAR T-cell therapy in the USA. Now he is working on an optimized version. He is also improving the manufacturing processes for CAR T cells at the Fraunhofer Institute for Cell Therapy and Immunology IZI. The goal: making the therapy accessible for more patients.

Professor Hudecek, what first brought you to the subject of cancer?

As a young physician, I was fortunate enough to work at the Fred Hutchinson Cancer Research Center in Seattle from 2007 to 2012. That was the cradle of bone marrow transplants. We developed the first CAR T cells in the laboratory there, and then one of the first clinical trials was conducted where CAR T cells were used in patients with hematologic cancers, generally called blood cancers. The project resulted an approved CAR T-cell product that is now being used to successfully treat many patients.

The new generation of CAR T cells could also be effective against solid tumors such as breast cancer or pancreatic cancer. How can this be achieved?

CAR T cells have to be much more effective for solid tumors than for blood cancers because they have strong resistance mechanisms. We have to give the CAR T cells special properties to get around this. We have to make them more efficient and extend their survivability. A second receptor that can recognize additional cancer structures could also be added to make the effect more specific. This demonstrates an advantage of immune cell therapy: We can combine properties and incorporate almost any number of qualities into a cell product. This distinguishes it from other therapies where a single substance works—or does not work.

How does this work against cancers that have already spread?

CAR T cells have a special quality here. A single tumor can be surgically removed, but the procedures become more complex where metastasis is involved. The new therapy could especially benefit patients with metastatic tumors. CAR T cells can recognize and fight metastases in the body.

Why are radiotherapy and chemotherapy used first instead of using CAR T-cell therapy right from the start?

We also get this question from patients. Despite all the euphoria, certain basic principles of medical practice have to be followed. A key rule is that the established therapy is used first, because we have many years of experience with it. Only then is the more experimental treatment used. Although it is very promising, it is also associated with risks. We must continue with this cautious approach, even though this is often difficult for patients with an unfavorable prognosis.

But we are making progress. Many studies indicate clear advantages for CAR T-cell therapy over chemotherapy and radiation. This therapy is now already being used in the second line of therapy for certain forms of lymph node cancer and multiple myeloma. This means that it is used if the initial treatment was not sufficiently effective or if the disease returns. There are already studies evaluating CAR T-cell therapy as part of the first line of therapy.

The therapy costs up to 400,000 euros per patient. Why is it so expensive?

First of all, the process is complex. Blood is first drawn from the patient in the clinic in a circulation procedure. The white blood cells it contains, the leukocytes, are enriched, hence the name leukapheresis. The material is then transported to a clean room laboratory where the cell product is manufactured under strictly controlled, sterile conditions.

That doesn’t sound especially complicated...

Oh, but it is. We are working with extremely sensitive reagents and need highly specialized personnel, technology, equipment and procedures. Finally, the cells are checked, frozen, released and transported to the clinic. The CAR T cells are not administered until after a preparatory treatment, a modified chemotherapy that reduces the patient’s existing immune cells. The choreography is complex. Every step has to be perfect. And the timing has to be right.

And this is where Fraunhofer IZI comes in? Optimizing production processes is a Fraunhofer specialty.

Right, yes. We are working on simplifying and standardizing the infrastructure with automated processes and logistics, without compromising medical quality. This has enabled us to almost halve the production time from the previous 12 to 14 days down to 7 to 10 days. Soon it will only be 3 or 4 days. We also use a novel method for genetic programming of the immune cells. Instead of using modified viruses as usual, we use non-viral mRNA and DNA vectors. This makes the therapy more tolerable for patients and also helps to reduce costs, as mRNA and DNA vectors are much easier to scale up and certain safety precautions are no longer necessary.

But the procedure is still expensive. Can our healthcare system handle it?

If we balance the costs with the benefits and the healing success of the therapy, and then compare that with other therapies, CAR T-cell therapies perform well. Combined therapies involving up to three or four drugs are used for cases of lymphoma or multiple myeloma, resulting in very high annual therapy costs. Patients have to go to the clinic every month. In comparison, the costs of treatment with CAR T-cells are in many cases even lower than those of conventional therapy.

What does the future hold? What are the next steps?

We are already researching the next stage, which is in vivo gene transfer. The gene transfer vector is administered intravenously directly into the patient’s body. The CAR T cells are then produced in the body.

So the human patient is their own cell factory?

Exactly. Initial case reports indicate that this can work well.

Could CAR T cells also be used preventively?

Yes, we are already working on corresponding ideas. Many things are possible using AI. Our vision for the future is of AI being able to generate a risk profile for each person using data from medical examinations, such as blood counts, imaging procedures and genetic tests. Based on this, we could then determine whether the risk of a particular cancer is so high that it is appropriate to treat it with CAR T cells, That is preventive medicine.

Will CAR T cells become the dominant cell therapy?

CAR T cells are currently the leading and most exciting form of cell therapy. The potential is enormous. CAR T-cell therapy can in principle be used for any form of cancer and also for treating non-malignant diseases such as infections and autoimmune diseases. Thus far, we have clear clinical proof of efficacy and approvals for treatment of certain forms of leukemia, lymph node cancer and multiple myeloma. We are still conducting intensive research and are working together with colleagues from the research community on new clinical trials and increasingly optimized products and processes. I am quite certain that we will soon see further approvals in various areas of medicine.

How does the avant-garde of cancer research fit in the Fraunhofer model?

Perfectly! The transfer to medical practice has always been important to me, to give as many people as possible the chance of a cure. That wish led me to Fraunhofer. Scientific excellence is not visible or meaningful for society until it is put into practice.

Prof. Michael Hudecek, pioneer and bridge builder for CAR T-cell therapy