Project Details
Projekt
Virus-based combination immunotherapy: A systems-level approach to tumor microenvironments in treatment-refractory cancer
Applicant
Dr. Hans Martin Singh
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 540928754
Background: The success of solid tumor immunotherapy is limited by an incomplete understanding of tumor microenvironments (TMEs) and their dynamics. This leads to treatment failure in refractory patients. It also slows the development of therapies with added clinical benefit. As one example, replicating virus-based agents (oncolytic viruses [OVs]) have been found to remodel TMEs in various respects, but have not improved the clinical outcomes of current immunotherapy in randomized trials. Specific aims: This project is designed to investigate and circumvent solid tumor resistance to state-of-the- art immunotherapies. The specific objective is to address primary and adaptative resistance mechanisms that are rooted in TME plasticity, involve interaction across cell type boundaries, and impair successful clinical treatment. Hypothesis: It is hypothesized that OV therapies are capable of breaking tumor immune resistance arising from the cooperation between TME cell types in specific settings. Experimental strategy: Patient-derived materials and syngeneic murine tumors will serve as complementary systems for functional and molecular immune profiling. Analysis of human tissue will focus on tumor specimens from patients undergoing clinical immunotherapy. In parallel, experimental therapies (incorporating adoptive T cell therapy and immune checkpoint inhibition) will serve as in vivo perturbations in murine cancer models. In synthesis, this strategy will allow to actively select for resistant tumor subsets, and to focus the evaluation of OV-based therapies on these settings of clinical relevance. To test the above hypothesis, an available platform of OVs including modified measles virus and vesicular stomatitis virus will be leveraged for targeted immune modulation of tumor ecosystems in both patient- derived and murine tumors. Read-out methods: TME evolution and selected resistance phenotypes will be studied using an iterative, data-driven, systems-level approach. Accounting for the complexity of tumor ecosystems, an integrative characterization of both single-cells and tissue architecture will be performed. Emphasis will be put on immune cell compartments in terms of cell phenotypes, functional states, and interactions. Molecular profiling results will be used to infer cell networks relevant to TME-mediated resistance under tumor immunotherapy. The specific effects of selected virotherapies on these TME cell networks will be determined. Relevance of projected results: The outcomes of this study could support the development of existing clinical regimens and produce rationales for novel combination immunotherapies.
DFG Programme
WBP Fellowship
International Connection
USA
