Engineering von ROR1-spezifischen CD8+ T-Zellen zur adoptiven Immuntherapie bei chronischer lymphatischer Leukämie

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The use of antibody and T-cell based therapies for the treatment of cancer is attractive because of the unique potential of the immune system to distinguish normal from diseased cells. Monoclonal antibodies targeting CD20 are now routinely used to treat B-cell malignancies and the adoptive transfer of genetically modified T-cells that express a chimeric antigen receptor (CAR) with an exodomain comprised of a single chain variable fragment of an antibody specific for a cell surface molecule linked to the T-cell CD3 zeta chain and/or co-stimulatory domains is being tested in clinical trials. A disadvantage of targeting lineage-specific molecules on B-cell tumors with immunotherapy is that normal B-cells are also eliminated. The orphan tyrosine kinase receptor ROR1 was identified as a highly expressed gene by expression profiling of Bcell chronic lymphocytic leukemia (B-CLL) and is also expressed on mantle cell lymphoma and a subset of B-cell acute lymphoblastic leukemias, but not in any normal adult cells. ROR1 is uniformly expressed at the cell surface on primary B-CLL, and we have developed a CAR that confers specific recognition of primary B-CLL when expressed in T-cells. In this project, we will develop ROR1-CARs that are optimized for tumor cell recognition and T-cell signaling, and evaluate the safety of ROR1-specific adoptive T-cell therapy in a pre-clinical model.