Enhancing CAR T-cell expansion and prolonged persistence for the effective treatment of paediatric medulloblastoma
1. We hypothesise that IL13RA2 can be leveraged as a safe and effective CART therapy against group3 MB
2. We hypothesise that epigenetic priming with AZA may represent an effective neoadjuvant therapeutic approach when complemented with CART therapy.
- To identify the optimal transmembrane and stalk CAR T-cell combination for sustained cytotoxity and proliferation advantage in organoid models of group3 medulloblastoma.
- To re-engineer the optimal CAR T-cell combination with next generation exhaustion-resistant mechanisms, with functional characterisation in co-culture organoid models of T-cells with group3 medulloblastoma.
- To analyse the enhanced efficacy of epigenetic modifiers in combination with the next generation CAR T-cells, using in vitro functional characterisation and methylation profiling.
- To evaluate the efficacy, persistancy and anti-tumour activity of the next generation CART plus epigenetic enhancer in vivo using multiple metastatic mouse models of group3 medulloblastoma.
6 - 12 month plan (eg experimental approaches, data collection, preliminary analyses):
To evaluate an array of therapeutic approaches in a high throughput setting, three-dimensional MB organoid cultures will be used to evaluate both T cell engineering and epigenetic drug approaches to enhance CAR-T persistence. This high-throughput system for CART screening is the latest advancement for cancer therapeutics, utilizing cell culture models which more closely mimic the in vivo micro-environment.
Year 1: Aim-1 and Aim-2
Year 2: Aim-2 and Aim-3
Year 3: Aim-4
Ethics Approval: REC 14/WM/1253
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