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Bone marrow transplants are often the preferred treatment for patients with severe combined immunodeficiency or acute myeloid leukemia (a cancer of the blood and bone marrow). This transplant consists of taking blood stem cells - called hematopoietic stem cells - from the bone marrow of healthy donors before injecting them into the patient. These cells then differentiate into functional red blood cells, platelets and lymphocytes, ultimately replacing the diseased blood cells.
“The problem is that T cells that guard our immunity take much longer than the others blood cells to reconstitute a functional stock: several months in children and up to two years in adults," says Isabelle André, director of the Human Lymphohematopoiesis Laboratory at the Imagine Institute. During this critical period, patients are extremely vulnerable and can be the target of severe, sometimes fatal viral infections and cancer relapses.
This inertia is explained by the process itself of lymphocyte production after a transplant. This process begins in the bone marrow, where each hematopoietic stem cell gives rise to T cell precursors called "progenitors". These progenitors then migrate to the thymus, an organ located above the heart, where they differentiate into T cells and learn to recognize pathogens: tumors, infected cells, etc. As a result, the T cell pool takes time to build up.
In a new study published in Cellular & Molecular Immunology, Isabelle André and her team describe a cell culture process that significantly reduces this delay. This could therefore reduce the risk of infection. Their approach consists in injecting patients with progenitors instead of hematopoietic stem cells. This requires producing them in sufficient numbers. To do this, they have mimicked in vitro the biological process of progenitor production and optimized it.
“Until now, each stem cell produced less than a dozen progenitors, which is not enough for clinical applications, particularly in adults," explains the researcher. "However, we found a way to increase this number tenfold by adding a protein called TNF-α to our culture medium, which already received a patent in 2018." As a result, the renewal of the lymphocyte stock after a transplant is up to ten times faster.
Patients could avoid heavy immunosuppressive treatments
Two clinical trials have just begun at Imagine Institute to test this approach. The first includes patients with severe combined immunodeficiency. It is coordinated by Despina Moshous, University Professor and hospital practitioner in the Pediatric Immunohematology and Rheumatology Department at the hospital. Within the Biotherapy Department of this same hospital, the grafts are prepared in the Cellular and Gene Therapy Laboratory, directed by Pr. Marina Cavazzana. The second trial is dedicated to patients with acute myeloid leukemia. It is led by Prof. Olivier Hermine, Director of the Hematology Laboratory at Imagine Institute and Head of the Adult Hematology Department at Necker-Enfants Malade hospital. A third trial is planned in the United States. It will be set up by SmartImmune, a start-up founded in 2017 by Isabelle André, Marina Cavazzana and Karine Rossignol.
For Isabelle André, "all these clinical trials are the completion of more than fifteen years of research initiated in 2005, with an overall budget of nearly ten million euros, and a nice team behind it." This project is a perfect example of the virtuous circle advocated by the Imagine Institute: starting with the patient to fuel research, identifying new therapeutic targets, implementing them and then returning to the patient.
