Amy DeZern, M.D., M.H.S.
2020 Funding recipient
A novel cell-based immunotherapy for the treatment of patients with myelodysplastic syndrome (MDS) directed against CD123
Discovery Research Grant 2020
The myelodysplastic syndromes (MDS) are a mixed collection of clonal blood malignancies that comprise a large subgroup of the myeloid cancers; collectively, they are the most common acquired adult bone marrow failure syndromes. They are characterized by decreased overall survival due to lesser ability to make new blood, progressive low blood counts, and transformation to acute myeloid leukemia (AML). Currently, only three agents are approved for the treatment of MDS by the U.S. Food and Drug Administration (FDA): azacitidine, decitabine, and lenalidomide and none based on specific markers of an individual patient’s disease. Allogeneic bone marrow transplantation (BMT) remains the only cure. Our increasing knowledge of the biology of MDS allows exploration of additional therapeutic approaches and lead to a more rational treatments.
A newer treatment opportunity has recently been introduced into blood cancer therapeutics called chimeric antigen receptors T cells (CAR Ts). These are manufactured constructs that, when introduced into a type of immune cell called T cells, enable recognition and killing of target cells in highly specific way. This allow us to target CAR T cell therapy against markers on a tumor cell. We now know that that CD123, a cell surface marker, is expressed on the earliest MDS stem cells as well as some normal cells. Previous experiments have shown that healthy donor-derived CD123 CAR T cells kill primary CD123+ MDS stem cells.
The objective of this proposal is to deliver a novel CAR T cell therapy to patients with MDS failed by currently available therapies. The intended goals are to safely administer this treatment both for disease control as well as improvement of the disease-related marrow failure. We will perform experiments to further confirm that it is possible do this in the lab first and then conduct a clinical trial with this CD123 CAR T cell therapy for patients with high risk MDS. We will also do additional tests on the blood of the patients treated on the trial to better understand the biology in responding and non-responding patients. The efficacy of killing the MDS stem cells in patients, immune system changes, and the elimination of malignant cell populations will be quantified.