Novel immunotherapy for paediatric cancers

Chimeric antigen receptors (CAR) are synthetic receptors that redirect T lymphocytes to specific tumour antigens. CART cells targeting CD19 (CAR19) have demonstrated remarkable efficacy against B cell malignancies in clinic. Currently used methods of CAR gene transfer to T cells based on viral vectors are complicated by the time and expense involved in the elaborate protocols required for their implementation.Non-viral transposon technologies may potentially offer a simpler and economical method for generating CART cells. Originally generated CAR19 using piggyBac (PB) transposon system had poor in vivo efficacy and persistence. Here we show that modifications in CAR constructs removing IgG1 Fc and incorporation of CD28 or 4-1BB co-stimulatory domains improve the in vivo potency of PB-CARs. At diminishing doses, 4-1BB co-stimulation led to greater potency and persistence of CART cells compared to CD28. These pre-clinical data provided the basis for testing PB transposon-based CART cells in clinical trials. CART cell therapy does not always induce sustained remissions, and the Event Free Survival (EFS) post-CART cell therapy correlates with CART expansion/persistence. The intrinsic T cell fitness prior to CART cell infusion determines the in vivo CART cell expansion and persistence. Little data exist, however, defining the role for leukaemia-specific factors in determining the outcome of CART cell therapy. Gene expression analysis has demonstrated significant heterogeneity in the expression of multiple immune co-signalling ligands by leukaemia cells derived from individual patients. High CD86, CD70 and ICOSL was associated with bad CART cell persistence while OX40L and IL10 expression - with good CART cell persistence and delayed CART cell exhaustion. Inclusion of 4-1BB in CAR design reduced CART activation but delayed their exhaustion. It also reduced CART cell dependence on external immune modulators. The significance of identified leukaemia-derived immune ligand expression for CART cell therapy outcomes will be validated using patient’s samples derived from clinical trial of PB transposon-based CART.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2019

Author dc:creator

• Tse, Benjamin Hong

• PiggyBac transposase
• Ehimeric antigen receptor
• Acute lymphoblastic leukemia
• Non-viral vector
• CD19
• B cell malignancy
• CAR T cell
• Murine xenograft model
• Mellular immunotherapy

Statement dc:rights

• open access
• CC BY-NC-ND 3.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by-nc-nd/3.0/au/

Language dc:language

EN

Identifier

https://doi.org/10.26190/unsworks/22316

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/70591