Medical and health sciences
- Applied immunology
- Cancer therapy
Engineering and technology
- Cell, tissue and organ engineering
- Cellular therapy
- Medical molecular engineering of nucleic acids and proteins
Mammalian cells modify their cell-surface and secreted proteins with extensive post-translational modifications of carbohydrate nature: glycans. As we have now gained an increasingly detailed insight into their biosynthesis and functionality, the structure of these glycans can be precisely engineered to impart optimized functionality to the proteins that carry them. This is especially useful in the biopharmaceutical field, where manipulation of glycans can be used to customize protein therapeutics. In the present project, we start exploring this synthetic biology of glycans in the context of therapeutic cells, i.e. CAR-T cells used in the treatment of cancer. We target a key limitation in CAR-T efficacy, i.e. their sensitivity to immunosuppressive activity of tumor-infiltrating regulatory T cells. We will explore two glyco(protein) engineering modules to target these regulatory T cells. First, we will use production by core fucosylation-knockout CAR-T cells of ADCC-potentiated afucosylated anti-CCR8 nanobody-Fc fusion protein, to kill tumor Tregs. Second, we will engineer CAR-T cells to produce glyco-engineered IL-2 variants that can no longer bind to the Treg-selective CD25 IL-2Ralpha chain, depriving Tregs from potent IL-2 stimulation, while leaving IL-2 stimulation of effector T cells untouched. The behaviour of these engineered CAR-T cells will be evaluated in vitro and in in vivo in immunocompetent, syngeneic non-Hodgkin lymphoma-bearing mice.