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Identification of super-agonist peptides for cancer vaccines

Galloway, Sarah 2020. Identification of super-agonist peptides for cancer vaccines. PhD Thesis, Cardiff University.
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Abstract

Background – T-cell-based immunotherapies are considered the biggest breakthrough in cancer treatment in recent decades. T-cells recognise peptide epitopes derived from tumour associated antigens (TAAs) displayed on human leukocyte antigen (HLA) molecules on the surface of tumour cells. Cancer peptide vaccines have attempted to use TAA-derived epitopes to activate cytotoxic T-cells, however these therapies have been largely unsuccessful. TAA are often self-proteins and therefore the resulting peptide epitopes are poorly immunogenic. Tumour infiltrating lymphocyte (TIL) therapy has resulted in remarkable cancer remission in some stage IV metastatic melanoma patients. Through an ongoing collaboration with the CCIT in Copenhagen, I had access to samples from long-term (7+ years) survivors following TIL therapy treatment for metastatic melanoma. Dissection of the TCR clonotypes of one patient, MM909.24, identified dominant and persistent TCR clonotypes in the TIL infusion product and PBMC post-cure. The aim of my study was to use one such TCR clonotype, ST8.24, to design super-agonist peptides to improve the efficacy of cancer peptide vaccines. Results – Combinatorial peptide library (CPL) screening of ST8.24 identified ten candidate super-agonist peptides. The optimal super-agonist peptide was determined using HLAEAAGIGILTV-pMHC tetramer staining of peptide primed polyclonal CD8 T-cells from healthy HLA A2+ individuals. The super-agonist peptide primed more EAAGIGILTV-tetramer positive cells than the wild type antigen in every individual tested. Super-agonist primed T-cells from healthy and melanoma patient samples were then found to be functionally superior. I sought to decipher the mechanism of the super-agonist peptide and discovered that it possessed remarkable structural mimicry to EAAGIGILTV. Furthermore, priming with the super-agonist peptide elicited T-cells specific for other TAA-derived epitopes. Finally, the peptide was shown to elicit superior T-cells in samples from renal cell carcinoma (RCC), chronic lymphocytic leukaemia (CLL) and acute myeloid leukaemia (AML) patients. Conclusions – I showed that it is possible to design a potent super-agonist peptide using CPL screening of CD8 T-cells. This peptide can break T-cell tolerance, eliciting functionally superior T-cells which recognise epitopes from different TAAs. These data show that superagonist peptides make attractive candidates for pan-cancer peptide vaccines and warrant further investigation.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 8 December 2020
Last Modified: 08 Dec 2020 15:13
URI: http://orca.cardiff.ac.uk/id/eprint/136880

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