GPNMB CAR-T Cells as a Multi-Pronged Immunotherapeutic Approach for Glioblastoma

Glioblastoma (GBM) is the most common and deadly adult brain cancer. GBM is particularly challenging because it contains many different cell types that help it grow and resist treatment, one of which are immune cells called macrophages. We identified a protein, GPNMB, found on the surface of both cancer cells and macrophages. We designed Chimeric Antigen Receptor (CAR)-T cells, immune cells engineered to recognize and kill cells that express GPNMB. Our preliminary data show anti-GPNMB CAR-Ts can simultaneously target both GBM cells directly, and macrophages. To further develop this treatment towards the clinic, our project has three main goals: First, we want to understand how anti-GPNMB CAR-Ts work inside the brain tumour. We will treat mice with GBM using anti-GPNMB mouse CAR-T cells, then study how the tumour and its environment respond. We can examine the gene expression of thousands of cancer and non-cancerous cells in the brain, and map where they are located. This will help us learn how a GBM brain responds to treatment and how it might resist therapy.

Secondly, CAR-Ts are normally made from a patient’s own blood, which can be time-consuming, expensive, and less efficacious. We will make CAR-T cells from healthy donors instead, and genetically engineer them to work better and last longer in a patient’s body. This approach will make the therapy stronger, faster, and more affordable. Thirdly, we will test these off-the-shelf CAR-T cells in mouse models that mimic human GBM. These mice have been transplanted with human immune cells, so we can observe how the CAR-T would target both human GBM cells and human macrophages in a patient. Our goal is to develop a powerful treatment that can overcome GBM’s defences. This research lays the groundwork for future clinical trials that could provide a life-saving option for GBM patients.