Exploring gene therapy approaches for neuroblastoma using a patient's own gamma delta T cells. (360G-Wellcome-105749_Z_14_Z)

Neuroblastoma is a rare childhood malignancy with tumours developing from the sympathetic nervous system. Approximately 50% of patients are affected by high-risk disease characterised by widespread metastasis. Five-year survival is only 40% despite highly aggressive multi-modal treatment regimes. Novel therapies that effectively target malignant cells whilst sparing normal tissues are therefore a research priority. Adoptive cellular therapy with T-cells engineered to express a Chimeric Antigen R eceptor (CAR) combine the antigen specificity of a monoclonal antibody together with T-lymphocyte cytotoxicity. Current approaches utilise alpha-beta T-cells due there abundance in the peripheral circulation and ease of expansion ex vivo. Gamma delta T-cells (gdT) however have many unique and advantageous properties, including innate killing ability, antibody-dependent cytotoxicity and professional antigen presenting function. When engineered with a CAR, gdT- cells may therefore may confer therap eutic advantage as we hypothesise they will give better tumour responses and better long-lived protection. This pre- clinical project investigates CAR-gdT-cells as a potential novel therapy for high-risk neuroblastoma. The ultimate aim is to engineer gdT-cells that have greater specific cytotoxcity, reduced off-target effects, and the ability to generate secondary immune responses leading to long-lasting anti-tumour surveillance. If successful, we will look to opening a CAR-gdT-cell phase 1 clini cal trial.