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Alice Vitali - CAR and TCR T cell therapy - competitors bundle forces. A combinational approach to prevent tumour escape by antigen loss

PhD project 12: neuroblastoma

Institute:The Institute of Cancer Research
Supervisor:Dr. Annette Künkele
Co-Supervisors:Prof. Dr. Monique den Boer and Prof. Dr. Hubert Caron
Doctoral Program:Berlin School of Integrative Oncology
Secondments:PMC (Netherlands) and Gadeta (Netherlands)

We want to enhance efficacy of adoptive T cell therapy against neuroblastoma by dual-specific T cells targeting intra- and extracellular antigens. We will engineer T cells expressing either an L1CAM-specific CAR or a TCR against a cancer testis antigen (MAGE-A1 or NY-ESO) or a combination of both. CAR and/or TCRs will be cloned into vectors and introduced into primary T cells by lentiviral transduction. Neuroblastoma cell lines will be screened for expression of MAGE-A1 and/or NY-ESO and HLA-A2 (RT-PCR, flow cytometry). T cells harbouring the CAR and/or the TCR will be compared for anti-cancer efficacy in co-cultures with neuroblastoma cells, 3D-printed tumours and patient-derived organoids (bioluminescent-based cytotoxicity assay, multiparameter flow cytometry, ELISA). We will test if IFNG secretion upon L1CAM recognition in the combined approach will result in HLA upregulation in MHC low expressing neuroblastoma (flow cytometry) making them susceptible for TCR-mediated killing. Efficacy of our combined approach will be tested in an NSG mouse model and compared to monospecific T cell therapy.

Expected Results
We expect to obtain results that demonstrate that our combined approach makes neuroblastoma vulnerable to TCR T cell-mediated killing and prevents escape by antigen loss.