ID #371 Testing combinatorial immune-cell strategies to overcome antigen escape and tumour heterogeneity in paediatric brain cancer

Abstract

Paediatric high-grade gliomas (pHGG), including Diffuse Intrinsic Pontine Glioma (DIPG), remain among the deadliest childhood cancers, with limited treatment options. Immune cell therapies such as Chimeric Antigen Receptor (CAR) and T-cell receptor (TCR) T cells offer new hope, but progress has been limited by tumour antigen heterogeneity, immune evasion, and a lack of preclinical models that reflect the human brain tumour microenvironment (TME). CAR T cells target surface antigens and TCR-engineered T cells recognise intracellular antigens presented on specific HLA molecules. We therefore hypothesise that combining CAR and TCR T cell approaches can overcome antigen escape and improve tumour killing in solid cancers.

Preferentially Expressed Antigen in Melanoma (PRAME) is a key TCR T cell target that is highly expressed in a range of cancers, with limited expression in healthy cells. The tyrosine kinase receptor EphA2 and glycosphingolipid GD2 are two CAR T cell targets that have shown great promise in early-phase clinical trials. As an essential first step, we have screened a panel of DIPG cell lines for HLA and PRAME expression to identify suitable models for testing HLA-A2 restricted PRAME TCR T cells, and for EphA2 and GD2 expression. These validated models will next be used to compare the efficacy of PRAME-specific TCR T cells alone and in combination with CAR T cells in our assembloid model that combines HGG gliomaspheres with human stem cell-derived cortical organoids. By integrating physiologically relevant DIPG models with engineered T cells, this work will identify optimal antigen HLA targets and accelerate translation of dual TCR and CAR T cell immunotherapies for paediatric solid brain tumours.