Enhancing CAR T Cell response by targeting expression of adhesion molecules in DLBCL

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymhoid malignancy, making up around 30% of all non Hodgkin lymhomas.

While first line therapy with R-CHOP immunochemotherapy achieves complete remission in around 60% of cases, refractory or relapsed patients (r/r) have a poor prognosis. For these r/r patients, immunotherapy with chimeric antigen receptor (CAR) T-cells has been established. CAR T cells are genetically engineered T-cells expressing the CAR, which is targeted against a tumor-specific antigen, e.g. CD19 in the case of DLBCL.

CAR T-cell therapy achieves a highly specific immune response against the malignant tumor. However, several resistance mechanisms can negatively affect this therapeutic strategy: One of them is a phenomenon called tumor-induced endothelial cell anergy, which is characterized by a lack of adhesiveness, expression of immune inhibitory molecules and unresponsiveness to inflammatory cytokines. We intend to target this physical barrier between T-cells and tumor tissue by inhibiting VEGF, a main mediator of endothelial cell anergy that is overexpressed by DLBCL cells. By combining antioangiogenic agents, TNFα agonists and CAR T cell therapy we aim to enhance the expression of adhesion molecules such as ICAM-1 to achieve increased immune infiltration of the tumor tissue and thereby, achieve better therapeutic results.