Antigenspecific non-signaling CARs as hemato-oncological remedy (ANCHOR project)(GILEAD award).

Acute myeloid leukemia (AML) is a rare type of cancer that predominantly affects people in the third age. The 5‐year overall survival rate of AML patients is only 30%, a figure that has not substantially changed despite enormous therapeutic advances in the last decade. Novel immunotherapies, such as T-cell receptor (TCR) T-cell and chimeric antigen receptor (CAR) T-cell therapies, are difficult to adopt in the context of AML. This is because most AML-related antigens are intracellular self-antigens that are expressed on the AML cell surface as peptides via major histocompatibility complexes (MHC); TCRs specific for these self-antigens are difficult to obtain since self-reactive T cells undergo thymic negative selection. In contrast to CD19 which is a very suitable extracellular target antigen for CAR-T cell therapy in acute lymphoblastic leukemia (ALL), the very few extracellular antigens expressed on AML cells that can serve as targets for CAR-T cell-based therapies, such as CD33 and CD123, are also expressed on normal hematopoietic stem/progenitor cells entailing a risk of intolerable myeloablation. The aim of this innovative project is to combine the best of two worlds, namely to redirect T-cells towards the key intracellular AML antigen Wilms' tumor protein 1 (WT1) using WT1-specific TCRs, combined with an innovative non-signaling CAR (NSCAR) towards a novel candidate extracellular AML antigen.

Keywords:CHIMERIC ANTIGEN RECEPTORS, IMMUNOTHERAPY, IMMUNOHEMATOLOGY, GENETIC ENGINEERING

Disciplines:Hematology, Applied immunology, Cancer therapy