Children with diffuse midline glioma, a fatal brain tumour, have a less than 5% chance of surviving five years after diagnosis. Radiotherapy offers only a temporary delay before the cancer returns. This project tests a new combination therapy: GD2-targeted CAR T cells—immune cells engineered to recognise the tumour—paired with a drug called navitoclax that kills senescent (aged) cancer cells left behind after radiation. The challenge is that navitoclax also harms the CAR T cells themselves. The researchers will engineer the CAR T cells to overexpress a protective protein, Bcl-xL, making them resistant to navitoclax while still able to attack the tumour. They will test this in 3D tumour organoids grown from patient cells. If successful, this approach could turn a temporary radiation response into a lasting one, potentially extending survival for children with this currently incurable cancer. The work is preclinical and fundamental—it asks whether a specific molecular strategy can overcome a toxicity barrier—but it directly addresses a bottleneck that has stalled clinical progress in paediatric brain tumour immunotherapy.
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Therapy-induced senescence is increasingly recognised in residual disease following radiotherapy or chemotherapy. Senescent cells, through the senescence-associated secretory phenotype, can drive tumor progression or escape senescence to cause relapse. Histone-3-mutant diffuse midline gliomas (DMGs) are fatal pediatric brain tumors with a <5% five-year survival rate. Radiotherapy remains the only treatment, providing transient benefits before recurrence. Recent trials in the US, UK, and Italy have explored GD2-targeted chimeric antigen receptor (CAR)-T cells in DMG, with early evidence of clinical and radiological responses. We have shown that DMG cells undergo senescence post-radiotherapy in vitro, in vivo, and in silico, and that BH3 mimetics, such as navitoclax, selectively eliminate senescent DMG cells via caspase-3/7 activation. In an orthotopic xenograft model, radiotherapy combined with navitoclax prolonged survival and reduced senescent tumor burden. However, both untransduced and GD2-CAR-T cells exhibit sensitivity to navitoclax at clinically relevant doses. Strategies to mitigate BH3 mimetic toxicity in CAR-T therapy have emerged, recently CD19-CAR-T cells combined with venetoclax showed reduced viability, which was rescued by overexpressing a venetoclax-resistant BCL-2 mutation (F104L). Furthermore, CAR-T cells developed to overexpress Bcl-xL, enhanced expansion and anti-tumor activity when combined with navitoclax in a leukaemia model. Building on this, we hypothesise that combining BH3 mimetics with GD2-CAR-T cells engineered with Bcl-xL overexpression will enhance DMG cell apoptosis and therapeutic efficacy. We will test this using 3D tumor organoids co-cultured with modified GD2-CAR-T cells and navitoclax in vitro.
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