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Development and preclinical testing of simultaneous dual engagement chimeric antigen receptors (SiDECARs) against acute myeloid leukemia

18th national competition for scientific and technical research

Immunotherapy and cancer

Senior Researcher : Hisse Martien van Santen

Research Centre or Institution : Centro de Biología Molecular "Severo Ochoa". CSIC-Universidad Autónoma de Madrid


CAR-T cell therapy is a new therapy to treat cancer. In this approach, the patient's immune cells are modified with a recombinant receptor ("chimeric antigen receptor" or "CAR") that combines antibody recognition domains with T-cell receptor (TCR) signaling domains. These cells can recognize proteins on the cell surface of the patient's tumor cells. which allows them to eliminate them. A limitation of this therapy is the lack of proteins that are only expressed on tumor cells, which leads to attacks by CAR-T cells on healthy tissues when they also express these proteins. Our first objective was to generate CARs that need to recognize two different proteins from AML tumors at the same time (SiDECAR) in order to restrict the activity of the CAR-T cell towards the tumor. However, the characteristics of this CAR are incompatible with its expression on the cell surface, an essential condition for its function. We work on an alternative approach in which the recognition domains are incorporated into two different receptors, one recognizing an AML protein and giving an activation signal and the other recognizing a protein expressed by healthy tissues, but absent from many AML and giving an inhibition signal to the CAR-T cell. We have optimized the activator protein and we are generating a panel of inhibitory receptors and will then combine them in T cells to test their activity against AML and healthy tissues. The second objective was to verify improvements in the signaling domains of the CARs. The data obtained clearly show that the function of the CARs can be improved, changing the signaling domain used in the vast majority of current CARs for another domain of the TCR with more diversity in signaling domains. This discovery has direct application in the design of therapeutic CARs.


Scientific Production
Magazine Articles -
Communications at national conferences 4
Communications at international conferences 4


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