Preclinical development of adoptive T-cell immunotherapy for EBV-associated diseases using third-party donors

Frumento, Guido (2018). Preclinical development of adoptive T-cell immunotherapy for EBV-associated diseases using third-party donors. University of Birmingham. Ph.D.

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Abstract

A significant number of patients requiring adoptive T-cell therapy (ATCT) need to resort to third party donors; we aimed to find ways to optimise ATCT from third party donors in EBV-associated diseases. Firstly, we evaluated the T-cell response to 29 EBV-restricted peptides in a cohort of 100 healthy donors. For each peptide we found at least one high-responding donor. Also, we compared the efficacy of different separation techniques. These results support the setting up of a registry of third party donors, to provide fresh EBV-specific T cells for ATCT. Secondly, we investigated the mechanisms generating T memory stem cells (T\(_S\)\(_C\)\(_M\)), which are considered most suitable for ATCT. We demonstrated that homeostatic cytokines revert recently differentiated CD8\(^+\) memory T cells from cord blood (CB) to cells with a T\(_N\)-like phenotype (T\(_N\)\(_r\)\(_e\)\(_v\)) and T\(_S\)\(_C\)\(_M\)-like characteristics. Finally, we compared phenotype and function of CD8\(^+\) T cells from peripheral blood and CB, after transduction of an EBV-specific TCR. Transduction efficiency, growth kinetics and cytolytic activity were comparable. However, TCR-transduced CB T cells showed less differentiated phenotype, increased multi-cytokine expression, and lacked expression of the senescence marker CD57. These data suggest that survival of engineered T cells in vivo is likely to be improved by using cells from CB.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):