Safe and effective immunotherapy for glioblastoma

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

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival of less than 18 months despite surgery, radiation, and chemotherapy. This project establishes a novel public-private partnership between QVQ, Amsterdam UMC, and Stichting ADORE to develop a next-generation CAR-T cell therapy for GBM. By combining a highly specific GBM-targeting CAR with a B7H3-based activation-inducible receptor (CAVIR), we aim to overcome major limitations of current CAR-T therapies, including tumor heterogeneity, antigen escape, and T cell exhaustion. This collaboration leverages complementary expertise in VHH binder development, receptor engineering, and preclinical GBM models to accelerate the translation of innovative immunotherapies.

GBM affects approximately 300,000 people worldwide each year and remains one of the most lethal cancers. Standard therapies rarely achieve long-term remission, and previous CAR-T cell therapies have shown limited efficacy in solid tumors due to heterogeneous expression of target antigens and off-tumor toxicity. The development of a safe, effective, and tumor-specific immunotherapy represents a critical societal need. Success in this project could significantly improve patient survival and quality of life while fostering innovation in European biotechnology and personalized cancer therapy.

Our approach is highly innovative and stepwise: first, novel VHH binders against B7H3 will be isolated, screened, and characterized for high specificity and binding affinity. These binders will then be incorporated into CAVIR constructs with optimized CTLA-4-based inducible expression upon T cell activation. Finally, T cells co-expressing a CAR and B7H3-CAVIR will be assessed in vitro and in orthotopic xenograft GBM models for safety, persistence, and anti-tumor efficacy.

Deliverables include a panel of high-affinity B7H3 VHH binders, optimized B7H3-CAVIR constructs, and engineered dual CAR+CAVIR T cells with validated functionality. Additionally, the project will explore the broader applicability of the CAVIR system for other neurological diseases, laying the foundation for future clinical translation and expanding the potential of next-generation CAR-T therapies.

Summary
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. B7H3 has emerged as a novel target for GBM. Here, we will generate novel nanobody (VHH) binders for GBM and apply them to a CAR+CAVIR strategy. We will generate and screen new VHH binders to target B7H3 (WP1). We will incorporate them in structurally optimized CAVIR constructs, and select the optimal binder (WP2). Finally, we will generate T cells carrying an EGFRvII-CAR and the selected B7H3- CAVIR and their ability to safely improve anti-tumor function and overcome tumor heterogeneity will be assessed in in vitro and in vivo GBM models (WP3). 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.
Technology Readiness Level (TRL)
1 - 4
Time period
36 months
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