Enhancing CAR T-Cell Responses by Targeted Inhibition of Angiogenic Factors in DLBCL

With a percentage of 35 % diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults with non-Hodgkin lymphomas.

For patients who do not respond to first-line therapy or experience relapse, chimeric antigen receptor (CAR) T-cell therapy has been established. This has led to breakthrough success in treatment responses in DLBCL patients with relapsed and refractory disease (r/r). CAR T-cells are genetically engineered autologous T-cells carrying synthetic receptors specific to a tumor antigen enabling a targeted immune response.

However, not every r/r DLBCL patient benefits from this therapy approach due to several resistance mechanisms, including the overexpression of vascular endothelial growth factor (VEGF). This could cause disorganized and leaky vascularization and a downregulation of endothelial adhesive molecules such as ICAM1, ICAM2 and VCAM, essential for leukocyte extravasation. This prevents immune cells from penetrating tumor tissue. By inhibiting the VEGF signaling pathway through antiangiogenic agents, vascularization can be normalized. We therefore aim to induce a more efficient penetration of immune cells, especially CAR T-cells, to overcome CAR T-cell resistance in DLBCL.