Project Details
Projekt
CAR T cell micropharmacies: Antigen-induced secretion of soluble VEGFR2 inhibitor for effective T cell invasion into solid cancers
Subject Area
Pediatric and Adolescent Medicine
Hematology, Oncology
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 523204368
Major barriers for effective targeting of solid tumors by chimeric antigen receptor (CAR) engineered T cells are the lack of T cell trafficking into the tumor microenvironment (TME) and their local inactivation by immunosuppressive components of the TME. This project develops an innovative strategy to amplify the anti-tumor activity of gene-engineered T cells by integrated secretion of VEGFR2 antagonist. We hypothesize that local inhibition of VEGFR2 will allow T cell infiltration and promote their function in the TME to result in tumor eradication. The hypothesis is based on the critical role of VEGFR2 in impeding T cell extravasation into solid tumors and creating a hostile tumor microenvironment. T cells will be engineered to express a CAR against the tumor-associated antigen GD2, along with the gene encoding for an inhibitory antigen fragment against VEGFR2. To locally enrich the VEGFR inhibitor in the tumor microenvironment, production will be inducible by CAR-mediated T cell activation, using a one-vector approach. The capacity of the modified T cells to lyse GD2+ tumor cells and produce and release inhibitory VEGFR2-specific antibody fragments in an antigen-specific, CAR-inducible manner will be demonstrated in vitro. In a mouse model, we will investigate to what extent release of anti-VEGFR2 promotes T cell infiltration into the tumor vasculature and how it affects myeloid cell components of the TME. Finally, we will assess the therapeutic antitumor activity of GD2 CAR/anti-VEGFR2 gene-modified T cells in in vivo models of Ewing sarcoma and neuroblastoma. Perspectively, this project is establishing the prerequisites for safe and effective clinical application of the novel strategy.
DFG Programme
Research Grants
