Targeting pancreatic adenocarcinoma with chimeric antigen receptor (CAR)-engineered Macrophages

• Applicant: Dr. Donjete Simnica
• Subject Area: Clinical Immunology and Allergology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559242053

The primary objective of this project is to develop and thoroughly investigate engineered primary human macrophages that are designed to target solid tumors, specifically pancreatic ductal adenocarcinoma (PDAC). Despite the success of six CAR T cell products approved by the FDA and EMA for treating hematological malignancies, similar breakthroughs for solid tumors remain elusive. One major challenge is the unique tumor microenvironment in solid cancers, which hinders the efficacy of therapeutic cells. Collagen, a predominant component of the extracellular matrix (ECM), plays a crucial role in this environment, with Discoidin-domain-receptor 1 (DDR1) recently identified as a key protein stabilizing collagen in the ECM. In this project, primary human monocyte-derived macrophages (MDMs) will be engineered to express chimeric antigen receptors (CARs) targeting DDR1 and mesothelin (MSLN), a known tumor-associated antigen in PDAC. We aim to comprehensively characterize these CAR MDMs to understand their mechanisms of action, including the role of specific signaling domains. Furthermore, we will assess their functional abilities—such as phagocytosis, cytotoxicity, and migration—towards PDAC cell lines and advanced 3D cancer models, including spheroids, patient-derived organoids (PDOs), and ex-vivo patient-derived tumor explants (PDEs). Finally, we will explore the potential of these CAR-engineered macrophages to cross-present tumor antigens to T cells, with the goal of triggering potent and diverse anti-tumor immune responses. This research will offer critical insights into the therapeutic potential of CAR-engineered primary macrophages, potentially opening new avenues for treating solid tumors like pancreatic cancer.

• DFG Programme: WBP Position