Arming therapeutic CAR-T cells with glyco-engineered suppressors of tumor-infiltrating regulatory T cells

At present, CAR-T cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. However, for solid tumors CAR-T therapeutic success remains low, with most success sofar in non-Hodgkin lymphoma (DLBCL, diffuse large B-cell lymphoma). Strong immunosuppression in solid tumors, in large part due to active Treg infiltration, is a major bottleneck.

We will optimize and evaluate the expression of an anti-CD19 CAR with simultaneous secretion of a fully functional afucosylated anti-CCR8 nanobody-Fc fusion protein that is potentiated for Fc-mediated function. On the other hand, we will engineer anti-CD19 CAR-T cells to produce glyco-engineered IL-2 variants that selectively bind to IL-2R-βγ, excluding engagement of the IL-2R-α. With both strategies, we envision to enhance anti-tumor efficacy of CAR-T cells by lowering the immunosuppressive Treg activity. These engineered CAR-T cells will be evaluated in vitro and in vivo in immunocompetent, syngeneic tumor-bearing mice.