Development of MHC class II-restricted TCR gene therapy for Epstein Barr virus associated malignancies
Year: 2016
Type: dissertation
Abstract: CD4+ T-cells play a pivotal role within the immune response, and multiple studies have highlighted their importance in anti-tumour immunity. TCR gene transfer is a successful method of specifically redirecting T-cell specificity. We have therefore investigated the anti tumour potential of EBV-specific MHC class II restricted T-cells, generated by this approach. We have identified and cloned a DR52b-restricted TCR, specific for an EBNA2 derived peptide (PRS), which is expressed in Post-Transplant Lymphoproliferative Disease (PTLD) \nand some other EBV-associated malignancies. \n \nWe have shown that the TCR is functional in both CD4+ and CD8+ T-cells, with transduced T-cells specifically recognising the PRS-peptide with a high avidity. Transduced T-cells have been shown to proliferate, produce multiple cytokines and have direct cytotoxic capacity in response to physiological levels of EBNA2 processed and presented by EBV-infected B-cells. Additionally to this direct response, CD4+ T-cells retain helper functions. Importantly, transduced T-cells have shown hints of tumour control \\(in\\) \\(vivo\\). \n \nResults from this study highlight that TCR gene transfer with EBV-specific MHC class II restricted TCRs can generate polyclonal T-cells with functional capacity against virus infected cells. PRS specific TCR gene transfer may thus be useful in rapid generation of T cells for treatment of PTLD. Given the importance of CD4+ T-cells for anti-tumour responses, this study also highlights the potential for using TCR gene transfer to target these \ncells towards other MHC class II-positive tumours.
Author: Anna Williams
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2339077645