Enhancing CAR T-cell expansion and prolonged persistence for the effective treatment of paediatric medulloblastoma
Hypotheses:
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.
Aims:
- 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.
Timeline
Year 1: Aim-1 and Aim-2
Year 2: Aim-2 and Aim-3
Year 3: Aim-4
Ethics Approval: REC 14/WM/1253
References:
- Donovan, L. K. et al. Nat. Med. 26, 720-731 (2020).
- Vladoiu, M. C*., El-Hamamy, I*., Donovan, L. K*. et al. Nature 572, 67-73 (2019).
- Northcott, P. A. et al. Nature 547, 311–317 (2017).
- Brown, C. E. et al. Clin. Cancer Res. 21, 4062-72 (2015).
- Brown, C. E. et al. N. Engl. J. Med. 375, 2561-2569 (2016).