Project Details
Projekt
Re-arming T cells to combat challenging cancer microenvironments
Applicant
Dr. Moritz Reichert
Subject Area
Hematology, Oncology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 576169509
Cancer immunotherapies have revolutionized treatment for many malignancies, but their efficacy is frequently limited by immunologically hostile tumour microenvironments (TME) that suppress T cell function and prevent effective cancer cell elimination. Mutant calreticulin-driven (mutCALR) myeloproliferative neoplasms (MPNs) represent an ideal model system to study these constraints. The cancer neoantigen is expressed on the cell surface of disease-driving stem cells providing a unique therapeutic opportunity, and targeted immunotherapies including monoclonal antibodies and bispecific T cell engagers have just entered clinical trials. However, advanced MPNs are associated with progressive fibrosis and an immunoregulatory TME, presenting significant challenges to immunotherapies and creating barriers to immune surveillance. Excess production of immunosuppressive molecules such as TGF-ß and galectin-1 by the cancer clone, along with reduced lymphoid support factors from niche cells, can compromise T cell-dependent therapies. This project will: (1) systematically characterize the immunoregulatory features of the mutCALR tumour microenvironment using multi-omic single-cell analysis of patient samples; (2) advance a novel human bone marrow organoid platform to evaluate targeted immunotherapies in disease-relevant tissue environments, and (3) test mitigation strategies focused on galectin-1 neutralization to overcome microenvironmental constraints in CAR T cells. The organoid model will enable spatial visualization of therapeutic penetration, T cell-target engagement, and the consequences of target cell killing on healthy hematopoietic stem cells and bone marrow stroma. The work will establish novel frameworks for understanding and overcoming tumour microenvironmental constraints on cancer immunotherapy, with immediate relevance for developing more effective treatments for MPN patients. The findings could have broad applicability to other malignancies characterized by fibrotic, immunosuppressive microenvironments, and provide a validated human tissue model aligning with regulatory transitions away from animal testing toward more clinically relevant preclinical platforms for immunotherapy development. This fellowship will complement my clinical training and research experience, allowing me to develop a research project in a world-class academic environment, acquiring cutting-edge techniques, and building international networks. This foundation will position me to establish an independent research group in the future, where I can bridge clinical and laboratory discovery, with the goal of developing immunotherapies for myeloid disorders.
DFG Programme
WBP Fellowship
International Connection
United Kingdom
