Re-education of immunosuppressive myeloid cells to increase the efficacy of chimeric antigen receptor (CAR) T cells.

• Applicants: Dr. Heiko Bruns; Professor Dr. Dimitrios Mougiakakos
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536993790

The therapy with chimeric antigen receptor (CAR) T-cells represents a revolutionary and promising treatment approach against cancer. Despite notable clinical successes achieved in certain subgroups of B-cell leukemia or lymphomas, we still face numerous challenges concerning the therapeutic efficacy of CAR-T cell therapy. A primary issue hampering the effectiveness of CAR-T cell therapy is the occurrence of severe, sometimes life-threatening toxicities. Additionally, inadequate anti-tumor activity, such as due to the loss of the target antigen, poses a significant obstacle. Moreover, interactions between the host organism and the tumor microenvironment play a crucial role in modulating the effector function of CAR-T cells. Tumor-infiltrating immune cells, particularly macrophages and myeloid-derived suppressor cells (MDSCs), are commonly found in the lymphoma microenvironment. These tumor-associated macrophages (TAMs) and MDSCs effectively suppress the T-cell response and contribute to the development of the cytokine release syndrome (CRS). To gain a deeper understanding of the interplay between TAMs, MDSCs, and CAR-T cells, this project pursues specific objectives. It aims to investigate precisely how these myeloid cell populations impair the function of CAR-T cells and whether the spatial arrangement of myeloid cells provides insights into the underlying mechanisms. Employing enzymatic biotinylation, the study aims to identify novel cell-cell interactions and examine the impact of myeloid cells on the emergence of antigen loss variants. Ultimately, the project seeks to not only negate the inhibitory function of myeloid cells through targeted modulation but also enhance the tumor-killing activity of CAR-T cells. This endeavor could be crucial in further optimizing the effectiveness and safety of CAR-T cell therapy, ultimately benefiting patients in need.

• DFG Programme: Research Grants