In 2017, the US Food and Drug Administration (FDA) granted approval for the first time for a completely new treatment for blood cancer in children who could no longer be treated with chemotherapy: they received immunotherapy with their own genetically modified T cells, so-called CAR-T cells. In most patients, the disease responded very well to the treatment – and in many cases, the therapeutic success was permanent, lasting for many years. There are now an increasing number of CAR-T cell therapies available for the treatment of leukemias, lymphomas and myelomas when standard therapy has failed. Even certain autoimmune diseases have been successfully alleviated.
One of the “fathers” of CAR-T cell therapies is the physician and immunologist Michel Sadelain, who is now working at Columbia University in New York. “Michel Sadelain has played a major role in giving patients with blood cancers hope of a cure, even in advanced stages of the disease,” says Stefan Fröhling, Chairman of the Meyenburg Foundation and Managing Director of the NCT Heidelberg. “The Meyenburg Award 2023 also particularly recognizes that Sadelain consistently focuses his work on quickly transferring the results of his research into clinical application.”
The idea of genetically modifying a patient's immune cells outside the body to increase their effectiveness against tumors was developed in the 1980s. Researchers equipped immune cells with artificially constructed T-cell receptors. This modular principle gave the therapy its name: “CAR” stands for “chimeric antigen receptors”. Their outward-facing portions came from an antibody. This made it possible for the first time to generate T cells against any surface antigen of the tumors. However, the first-generation CAR-T cells were short-lived and showed no clinical efficacy.
Booster for therapeutic cells
“The breakthrough came with an idea from Michel Sadelain,” says Stefan Pfister, director at the Hopp Children's Cancer Center Heidelberg and also on the board of the Meyenburg Foundation. ”Thanks to his innovations, CAR-T cells can now multiply sufficiently in the body and survive for a long time – both of which are crucial prerequisites for successful cancer treatment.”
Sadelain, who was then at the Memorial Sloan Kettering Cancer Center in New York, realized that the first generation of CAR-T cells were not sufficiently activated by contact with their antigen. So he added a third element to the chimeric receptor. This acts as a booster for the activation signal that is transmitted to the immune cell via the T-cell receptor. This was the decisive step that increased the effectiveness of the therapeutic cells. In 2003, Sadelain and his colleagues were able to show with their groundbreaking work that their second-generation CAR-T cells could successfully fight leukemia cells in a mouse model.
Further improving a highly effective therapy
As convincing as the effectiveness of CAR-T cells was in many patients, some weaknesses were observed time and again. These include the dangerous exhaustion of therapeutic cells, which is often the cause of treatment failure, or the development of resistance in cancer cells.
By intelligently refining CAR-T cells, Michel Sadelain was able to improve the effectiveness and safety of the treatment: He replaced the viruses previously used to insert the CAR gene construct into the patient cells with a targeted procedure using the CRISPR-Cas “gene scissors”. This allows the receptor gene to be integrated into a region of the genome where it can be better regulated by the cell, thus preventing the cells from “exhausting”.
In many cases, tumor cells escape the CAR-T cells by making the target antigen disappear from their cell surface. Sadelain was also able to prevent this frequently observed resistance mechanism by using a genetic trick to increase the sensitivity of the therapeutic cells tenfold.
“Today, well over a thousand clinical trials are underway worldwide with various CAR-T cells against different types of cancer at different stages. The method has great potential, but still fails, for example, in solid tumors,” says Fröhling. ”We all hope and wish that Michel Sadelain has many more ideas in store so that this highly effective form of therapy can benefit even more cancer patients in the future.”
About Michel Sadelain
Michel Sadelain received his M.D. from the University of Paris in 1984 and his Ph.D. from the University of Alberta, Canada, in 1989. After completing his surgical residency in Paris, Sadelain conducted postdoctoral research at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology (MIT) before moving to the Memorial Sloan Kettering Cancer Center in New York in 1994. In the fall of 2024, he moved to Columbia University, New York.
Sadelain has received numerous awards, including the William B. Coley Award for Distinguished Research in Tumor Immunology, the Pasteur/Weizmann Award, the Leopold Griffuel Award, and, in 2024, the Breakthrough Prize in Life Sciences, together with Carl H. June.
About the Meyenburg Prize
The Meyenburg Foundation, under the umbrella of the DKFZ, has been awarding the prize since 1981. The award for outstanding achievements in cancer research is one of the most highly endowed science prizes and one of the most important awards for cancer research in Germany.
The importance of the award is also demonstrated by the fact that numerous Meyenburg Prize winners have later been awarded the Nobel Prize: Andrew Fire, Meyenburg Prize winner in 2002 (Nobel Prize in Medicine in 2006), Elizabeth Blackburn, Meyenburg Prize winner in 2006 (Nobel Prize in Medicine in 2009), Shinya Yamanaka, Meyenburg Prize winner 2007 (Nobel Prize in Medicine 2012), Stefan Hell, Meyenburg Prize winner 2011 (Nobel Prize in Chemistry 2014), Katalin Karikó, Meyenburg Prize winner 2021/22 (Nobel Prize in Medicine 2023).
*The symposium will begin at 3:30 p.m. on April 2 in the DKFZ Communication Center.
The speakers are:
Michel Sadelain (Columbia University, New York)
Andreas Mackensen (Erlangen University Hospital)
Fabrice André (Institut Gustave Roussy)
Hafsa Munir (DKFZ and HI-TRON Mainz)
Franziska Blaeschke (DKFZ and Hopp Children's Cancer Center Heidelberg)
