The revenge of French immunologist Michel Sadelain

Often compared to the antechamber of the Nobel Prizes or the Oscars of science, the Breakthrough Prize for life sciences was awarded to a French doctor, Michel Sadelain (63), for his discoveries on CAR-T cells , at the origin of revolutionary therapies against cancer

The revenge of French immunologist Michel Sadelain

Often compared to the antechamber of the Nobel Prizes or the Oscars of science, the Breakthrough Prize for life sciences was awarded to a French doctor, Michel Sadelain (63), for his discoveries on CAR-T cells , at the origin of revolutionary therapies against cancer. This researcher, trained at Saint-Antoine hospital in Paris, flew to North America in the 1990s. For thirty years, he plowed his furrow. Often misunderstood, sometimes mocked, he ultimately saw his work on immune cells transform the treatment of certain cancers.

Le Point: You would never have received this award if…

Michel Sadelain: I had not been so stubborn. I had the idea thirty years ago of transforming certain patients' immune cells into weapons of war against their tumors. Normally, our immune system is not very good at fighting cancer because it is our own cells and not an external enemy like a virus or bacteria. So I had the intuition that it was necessary to “teach” T lymphocytes to give them the ability to “see” malignant cells and destroy them. Concretely, the therapy consists of taking lymphocytes from a patient. These lymphocytes are sent to the laboratory, where we genetically program them so that they can recognize cancer cells. Then, they are cultured for a few days to multiply before being reinjected as an infusion into the patient and attacking their cancer.

For twenty-five years, your work was carried out in relative indifference...

Only two oncologists, the Americans Carl June, of the University of Pennsylvania – co-recipient of the Breakthrough Prize –, and Steven Rosenberg, of the National Cancer Institute, believed in this technology. The gene therapy approach scared oncologists. And the majority of immunologists did not understand our approach. I suffered ridicule from many colleagues. It started with: “What a crazy idea to be interested in lymphocytes. » Then I got: “It won't work anyway”; or: “You won’t be able to do that in humans,” not to mention: “Industry will never be interested. »

But you did it! How did you go about it?

I first became an airframe engineer. After my medical studies in France and a thesis in immunology in Montreal, I went to the Massachusetts Institute of Technology (MIT) in Cambridge to learn how to manipulate genes myself. Subsequently, with my team at the Memorial Sloan-Kettering Cancer Center in New York, we manufactured a synthetic gene, unknown in nature, then we inserted it into the genome of T lymphocytes. Through testing and of repetitions on animal models, we succeeded, thanks to this gene, in transforming lymphocytes into CAR-T (Chimeric Antigenic Receptor -T) cells. These genetically modified lymphocytes attach to a protein called CD19, present on the cells of certain blood cancers (leukemia and lymphoma). They can then do their job and eliminate them.

In 2013, you published your first clinical trial… With what results?

The first five patients with acute lymphoblastic leukemia (ALL) included in our study were in relapse and, above all, they were refractory to all existing treatments. So there was no more hope. In a few days, with our treatment, their cancer regressed. Overall, early trials have shown that with CAR-T cells, these cancers become undetectable in 60% to 80% of patients.

Has everything been going wrong in the last ten years?

Suddenly, our work interested everyone. Today, there is really something to smile about when I think back to the mockery of certain colleagues about the impossibility of getting large pharmaceutical laboratories interested in both cellular and genetic therapy. Today, six drugs are launched. The Swiss Novartis, the Japanese Takeda Pharmaceutical and the American Bristol-Myers have launched into the market. More than a thousand clinical trials on CAR-T cells are currently taking place around the world. The challenge now is to extend this technique to solid tumors, but also to other pathologies, autoimmune or infectious.

Last year, in 2022, Katalin Kariko and Drew Weissman received the Breakthrough Prize for their work on messenger RNA which enabled the development of vaccines against Covid-19. Do you see a similarity in your backgrounds?

Obviously, we have in common that we have walked in our little corner for a long time. We got through to the end despite the difficulties. Today, with this prize, my great pride is to have allowed “living drugs”, based on cells and not only on chemistry, to leave fundamental research institutes and hospital laboratories to be developed at home. large scale.