Development of MHC class II-restricted TCR gene therapy for epstein barr virus associated malignancies

Williams, Anna (2016). Development of MHC class II-restricted TCR gene therapy for epstein barr virus associated malignancies. University of Birmingham. Ph.D.

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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)
and some other EBV-associated malignancies.

We 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 \(in\) \(vivo\).

Results 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
cells towards other MHC class II-positive tumours.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):