Michel Sadelain: “Living Medicine” Pioneer Explores New Frontiers at Columbia

In the past decade, Michel Sadelain has been at the center of a revolution in the treatment of cancer.

Sadelain’s research going back to the 1990s helped launch CAR-T cell therapy—a “living medicine” that instructs the patients’ own cells to seek out and destroy their cancer. The first CAR-T therapies were approved in 2017, and since then more than 45,000 patients with leukemia, lymphoma or multiple myeloma have been treated with the therapies. Most of these patients had run out of other options, and for some, the treatment has kept their cancer at bay for more than a decade.

In Oct. 2024, Sadelain moved to Columbia to advance his ideas to create CAR-T therapies that tackle more cancers and other diseases. He is the founding director of the new Columbia Initiative in Cell Engineering and Therapy (CICET) and director of the Cancer Cell Therapy Initiative in the Herbert Irving Comprehensive Cancer Center.

“What makes it so exciting to be at Columbia is the depth and breadth of the school. There's, of course, a terrific cancer center, but there's also an incredible program in transplantation, a lot of expertise in autoimmune diseases, in neurological disorders, all of which could benefit, perhaps, from the use of engineered immune cells,” Sadelain says.

“I'm really thrilled to be here, embedded in such a community at this time when immune engineering and the engineering of other cell types is just on the cusp of being introduced into so many fields of medicine. And Columbia is particularly well positioned with its wealth of knowledge and expertise in systems biology, stem cell biology, transplantation biology, biomedical engineering and artificial intelligence, to create these new therapies."

We recently spoke with Sadelain about his role in developing CAR-T therapies and his plans at Columbia.

You’ve often described the cell therapies you’ve developed as “living medicines.” Can you tell us a little about how CAR-T cells are made and what they can do?

CAR-T cell therapy is a novel form of immunotherapy, that is to say, a therapy that enlists your immune system in fighting disease.

The crux of CAR-T therapy is that the medicine is not a pill, it's not a chemical, it's not a protein—it's a cell. It's a human T cell and it's been reprogrammed to perform a certain task.

I think it was in 2012 when a reporter asked me, “So, what is it that you do?” I said, “I create living drugs.” And the term has stuck. Most drugs work only for a short while, and sooner or later degrade. CAR-T cells being alive, they can multiply and persist for weeks, months and sometimes years.

To create CAR-T therapy, T cells are extracted from the patient, brought into the lab and taught what to do. We introduce an artificial gene that tells the cells to produce a synthetic molecule, and that molecule tells the T cell where to go in the body to find the cancer cells and eliminate them.

This synthetic molecule is what we call the chimeric antigen receptor, or CAR. The AR stands for antigen receptor. These are molecules on the surface of T cells that detect antigens in diseased or infected cells. The C stands for chimeric because the synthetic molecules are generated by stitching together parts of proteins that are never assembled together in nature, exactly like those chimeras of mythology, with the head of a lion, the body of a bird, and the tail of a reptile. The synthetic CAR molecule gives T cells new capabilities beyond a patient’s natural T cells.

Why did people think that creating these cells was a crazy idea? Why are CAR-T cells so revolutionary?

When I shared with my colleagues this idea of engineering immunity, the response was pretty universally negative. People objected to our proposition of conceiving synthetic receptors: why create a new type of antigen receptor when there’s already a great one given to us by evolution. Or they raised concerns that inserting genes into cells is too dangerous.

Some went further and said, well, even if it worked, there's no way it could be implemented in practice. That's the toughest critique: to say, that even if you succeed, it will be useless. But I did think that there would be some virtue to all of this. Perhaps it was naiveté, but above all it was resilience and the conviction that, despite what some very smart people are telling you, they just don't see the potential.

That brings up my next question: what is the role of universities in nurturing these groundbreaking discoveries? I ask, because large segments of American taxpayers don’t think that supporting university scientists is very important right now.

I think the story of CAR-T therapy is a poster child for the importance of university research.

It is so important that the public at large realize that new medicines, most of the time, don't come from the pharmaceutical industry. The pharmaceutical industry distributes them to the public, but they originate from research conducted in medical centers and universities.

CAR-T research was not embraced—even within academia initially—it was considered too far-fetched. An investor who wants a return on their money in three years is not going to put a penny in this, and the pharmaceutical industry won't even come near an idea in its early stages until there’s some proof of principle.

When I started working on this at MIT decades ago, we struggled to overcome the first hurdle, introducing a gene into a T cell. We attempted this for several years, until finally, something started working.

Revolutionary ideas are generated in these early-stage settings. There's no new therapy if you don't have an early exploratory stage. So it's tragic that people think that tax dollars are wasted on early research.

By the time the pharmaceutical industry got involved, we had already built the cell-manufacturing facilities, tested the cells in patients, and produced results in the clinic. It is really, I think, a perfect example of how taxpayer dollars fund research that save lives, and that could be your family member or neighbor next door.

Since the first CAR-T cells were introduced to patients, they have had the most success with blood cancers. Why are other cancers more difficult?

Well, blood cancers primarily live in bone marrow, blood, the spleen, and lymph nodes. These are spaces we know T cells spend time in. That was one of many reasons for wanting to design the first CAR-T therapies for hematological malignancies.

Solid tumors live in different organs and are structured in a different way. We need to instruct T cells to overcome a number of molecular, metabolic, and sometimes physical barriers that they encounter in solids cancers.

The good news is that a lot of these barriers are recognized today, and now it's up to creative scientists and physicians to come up with the solutions.

It won’t happen overnight. It took 14 years to go from our landmark 2003 paper showing that human CAR-T cells can cure lymphoma or leukemia in a mouse to FDA approval in 2017.

In my own lab, we’re working on CAR-T therapies for leukemias, brain tumors, liver and ovarian cancer; we are also exploring treatments for inflammation, senescence-associated pathologies, and neurological disorders.

Do CAR-T cells have the potential to treat other diseases besides cancer?

It's really extraordinary today to contemplate all the possibilities that CAR-T cells have opened.

It turns out that CAR-T cells can be very useful for autoimmune disorders [when the patient’s immune system mistakenly attacks certain cells or tissues]. CAR-T research is most advanced in a condition called lupus, where there have been exciting initial results.

The CAR-T cell doesn’t have to be reinvented for these diseases; the recipe is the same as for cancer, but the cells must be carefully studied. And that's what's happening, including at Columbia, where we intend to intensify that effort.

Beyond lupus are other autoimmune diseases—myasthenia gravis, scleroderma, rheumatoid arthritis, multiple sclerosis and forms of neuritis, which are neurological disorders, forms of myositis, which are muscle diseases, and possibly some forms of colitis.

CAR-T cells could also be useful to solve problems in transplantation. There are still patients who have complications with accepting the grafts. With a CAR approach, other types of T cells could be trained to home in on the transplanted organ and lower the risk of rejection.

Any final thoughts?

Another important direction which underlies all of the above is, how do we lower the cost of these cells? The cost of drugs is a big challenge for all societies and making a cell is more complex than making a chemical.

Part of the solution lies in governmental affairs, insurance, states, other stakeholders. But another part of the solution lies in the biology, the part we're best positioned to tackle. If you make better cells, you will need fewer cells. And that will facilitate access to cell therapies. So we keep doing research to improve the efficacy and safety of engineered cells.