To be successful, a scientist must not just be brilliant. He often also has to be pugnacious, even stubborn, equipped with an ironclad shell to withstand the fiercest criticism and the lowest blows, and not be afraid to fight. Behind his gentle demeanor, his kind smile and his small rectangular glasses, Michel Sadelain undoubtedly combines all these qualities. This Frenchman, who has lived across the Atlantic since the end of his medical studies, has just won the Breakthrough prize in Life science. A prestigious scientific prize, seen as the precursor to the Nobel, which rewards his work on CAR-T cells, a revolutionary treatment against cancer.
More precisely, he is a co-winner – and we feel that for him, it is a detail that changes everything. Because the other winner, Carl June, turns out to be one of his direct competitors, who for years knew how to attract the spotlight and take credit for this invention. The jury, however, left out Steven Rosenberg, a researcher also very involved in this field. For a long time, this trio, Sadelain, June and Rosenberg, were allies. It must be said that at the start, more than twenty years ago, very few believed in their idea. They first collaborated to impose it, before competing for the authorship of the technique. A merciless battle for patents, markets, and scientific recognition.
The treatment consists of a complex mixture of cell therapy, gene therapy and immunotherapy. “These are T lymphocytes modified to give them the ability to identify tumors,” summarizes Michel Sadelain. T lymphocytes are the armed commandos of our immunity, which constantly circulate in our body to identify intruders (viruses, bacteria) and destroy them. But cancer cells, which develop from our body, often escape their vigilance. It was therefore necessary to give them the ability to “see” the tumors. To do this, Michel Sadelain first manufactured a synthetic gene, unknown in nature, which he introduced by gene therapy into the genome of these white blood cells. Thanks to this manipulation, the lymphocytes manage to dock with a protein called CD19 present on the surface of the cells of certain blood cancers (leukemia, lymphoma and myeloma). They can then eliminate them.
Spectacular results
The results of clinical trials have been very spectacular. In some patients, the tumors visibly regress within a few days. Today, six drugs are on the market, with complete remission rates ranging from 60% to 80% of treated patients. Research work is now going well all over the world to extend this technique to solid cancers but also to other pathologies, autoimmune or infectious.
Before getting there, Michel Sadelain had to overcome the taunts of many colleagues. “I did a thesis in immunology in Montreal, and I always had the idea that we should be able to ‘instruct’ T lymphocytes to attack cancers. So I went to the Massachusetts Institute of Technology to become a genetic engineer, because at the time, in the 1990s, it was really just starting up, and very few places in the world had mastered this technology,” he says. But even in this cutting-edge research center, no one really believes in his idea: “At best I was told that it was ‘preposterous’. Very eminent people even thought that I was wasting my time. Subsequently, some discouraged students to come and work with me,” he remembers. He quickly joined the Memorial Sloan Kettering Cancer Center (MSKC), in New York, one of the world’s largest cancer research centers, which he would never leave.
Ten years passed, busy manipulating lymphocytes in the laboratory and testing animal models, with another French woman, Isabelle Rivière, whom he would eventually marry. A period which takes place amid general indifference and the recurring quest for money. But success will be at the end of the road: his team published in 2003 the demonstration that it is possible to introduce human tumors expressing the CD19 protein into mice, and to eliminate them with modified human T lymphocytes. “This publication opens the way to clinical trials,” he explains. He chose to name his molecule CAR-T cell (chimeric antigenic receptor, T cells referring to lymphocytes).
At the time, two researchers were also working in the same direction, in Israel (Zelig Eshhar) and in Memphis (Dario Campana), but it was the work of Professor Sadelain which became a landmark. Two other immune system specialists, Carl June at the University of Pennsylvania and Steven Rosenberg at the National Cancer Institute (NIC), are closely following this research. It is still time for collaboration, and Michel Sadelain shares his molecule with Rosenberg so that he too can work on it. Carl June obtained one of similar construction from another researcher. “It wasn’t me who gave it to him directly, but it was really the same concept,” insists Professor Sadelain.
Legal battles
Steven Rosenberg has the full power of the NIC, and Carl June already has a lab to produce the modified T cells for testing. Michel Sadelain must start by building equivalent equipment in his hospital. In the race for clinical trials and publications, it was Steven Rosenberg first, then Carl June who arrived first, with almost miraculous cases of healing. Carl June in particular will attract the spotlight because he saves a little girl, Emily Whitehead, from leukemia. A success that he will widely publicize.
Money from big pharmas and investors then begins to flow freely. Rosenberg signs with Gilead, June with Novartis and Sadelain participates in the creation of a biotech, Juno. The rest will be managed through legal proceedings. Carl June, first, recognized that the CAR used in his first tests was not his invention. Then a resounding trial will take place in 2017 between Gilead on one side, Juno and the MSKC on the other so that Gilead’s fraudulent use of Michel Sadelain’s invention is recognized. A first court will agree with them in 2019 and sentence Gilead to a very heavy fine ($750 million, later reassessed to $1.2 billion). But the laboratory has relaunched legal proceedings, the case is still ongoing, and payment of the fine has been suspended.
In the meantime, Michel Sadelain claims to have benefited very little financially from his discovery. He is nevertheless delighted with the prospects it opens up today. Particularly in autoimmune diseases. Here, what was only a side effect of anticancer treatment, the destruction of B lymphocytes from which blood tumors arise, becomes the therapy. “The CD19 molecule is found on the surface of these lymphocytes which, in the context of autoimmune diseases such as lupus, will begin to produce autoantibodies, antibodies which target the patient’s own cells,” explains Michel Sadelain. Initial tests showed that CAR-T cells destroyed these B lymphocytes much more effectively than existing treatments. And this is just the beginning: some are already imagining using this arsenal to attack the cellular reservoirs where HIV, the AIDS virus, knows how to hide so well.
There remains the question of solid cancers. “For the moment it is not working. We ourselves did not want to launch clinical trials, because we were not convinced that the current recipe would be sufficient,” explains Professor Sadelain. Today, this is its great ambition: to adapt its CAR-T to organ tumors. “We are starting to better understand the subject,” he emphasizes. Three major challenges await scientists. First, find the right targets, molecules equivalent to CD19 in blood cancers. “We think that it will actually take three, which is proving very difficult to do in terms of CAR design, but we are working on it,” he explains. The lymphocytes must also succeed in reaching these solid tumors, which is not obvious depending on the organs affected, and finally, they must bypass the defense mechanisms implemented by the tumors. This is where CAR-T cells join so-called checkpoint inhibitor immunotherapies, commonly used today against different cancers (melanoma, lung, etc.), but with varying degrees of effectiveness: by combining these two weapons, Michel Sadelain, like other scientists, thinks it will be possible to obtain better results.
The scientist has only one regret today: not having been able to pursue his career in France: “My idea was too provocative 25 years ago. And even in the United States, it was not always simple to find money, the world of philanthropy, including the Arc Foundation, helped us a lot,” he emphasizes.