Team: Maria Themeli & Bart Westerman

CAVIR: CTLA-4-based activation inducible receptor for adoptive T cell immunotherapy of Glioblastoma

Adore is a partner in this promising and translational Health-Holland TKI project, which seeks to develop optimized CAR-T cell strategies with the potential to benefit a broad patient population.

Despite the success of immunotherapy with chimeric antigen receptor-engineered T cells (CAR-T) in hematology, several factors still hinder its application for solid tumors, such as: the heterogeneous target-antigen expression, the lack of tumor-specific targets and the reduced functional persistence of CAR-T cells. We have previously shown that dual-targeting with a CAR and a chimeric costimulatory receptor (CCR), can enhance CAR-T cell cytotoxicity and persistence but cannot overcome tumor heterogeneity. Expanding the potential of this strategy, we have developed the CTLA-4-ActiVation Inducible Receptors (CAVIR, patent EP22386075). This system exploits the activation-inducible trafficking of CTLA-4 by fusing its intracellular (IC) domain to chimeric receptors achieving their spatially controlled expression. The CAVI-R expression is induced only upon activation of T cells, for example through a CAR. This novel strategy provides with a local, tumor-specific lytic capacity, overcoming heterogeneous antigen expression patterns and improving functional persistence of CAR-T cells.

Glioblastoma multiform (GBM) is a brain tumor with highly heterogeneous expression of potential targets and an urgent unmet clinical need. Here, we will generate novel nanobody (VHH) binders for GBM and apply them to a CAR+CAVIR strategy. If successful, this project will generate not only a new treatment option for GBM but also for other solid tumors and will also generate critical knowledge for the improvement of CAR-T cell therapy for non-malignant neurological diseases.