Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. First-line therapy with the immunochemotherapy regimen R-CHOP produces long-term disease-free survival in about 60 percent of patients. Patients who relapse or develop refractory disease have an unfavourable prognosis with standard chemotherapy options. Recently, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapies have been approved in the treatment of relapsed or refractory DLBCL, providing durable responses in a subset of patients. However, still around 50% of patients after CAR T cell therapy are refractory against CAR T cell therapy.

Several mechanisms of CAR T cell resistance have been identified, including loss or downregulation of the target antigen, CAR T cell exhaustion and poor CAR T cell expansion. Notably, an immunosuppressive tumour microenvironment (TME) plays an important role in reducing CAR-T cell efficacy by contributing to functional exhaustion and limited expansion of these cells. Under pathological conditions, like cancer, immature myeloid cells can accumulate and promote an immunosuppressive function in the TME. Our research group has recently identified a population of lymphoma-associated myeloid monocytic cells which inhibit CAR T cell function and efficacy. These cells exhibit an increased expression of spleen tyrosine kinase (SYK), indicating a relevant role of SYK signaling for the function of immunosuppressive myeloid monocytic cells. 

Therefore, we aim to investigate the impact of SYK inhibition on the tumour microenvironment in DLBCL and to explore potential synergistic effects between SYK inhibition and CAR T cell therapy as a novel strategy to enhance therapeutic efficacy.  

https://innere1.uk-koeln.de/forschung/arbeitsgruppen-labore/krebstherapie-und-molekulare-bildgebung/