Use this URL to cite or link to this record in EThOS: | https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.723386 |
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Title: | The development of novel T cell receptor, and chimeric antigen receptor, engineered T cell therapies for the treatment of cancer | ||||||
Author: | Tubb, Vanessa |
ISNI:
0000 0004 6424 9948
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Awarding Body: | University of Birmingham | ||||||
Current Institution: | University of Birmingham | ||||||
Date of Award: | 2017 | ||||||
Availability of Full Text: |
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Abstract: | |||||||
The ability to generate a tumour-reactive T cell compartment is possible through the genetic engineering of patient T cells with tumour-reactive TCRs or CARs. The clinical testing of such therapies is garnering increasingly encouraging results, particularly in haematological malignancies. However, identification of more potent and specific target antigens, and combating immunosuppression in the tumour microenvironment is necessary to transfer these clinical responses to solid tumours. We investigated whether recurrent cancer mutations encode immunogenic neoantigens presented by common HLA class I alleles. We isolated TCRs specific for putative neoepitopes derived from common mutations in calreticulin (mCALR), and FBXW7. These TCRs showed moderate affinity but fine peptide specificity for mutant peptides, with some TCRs capable of recognising mutant cell lines. However, mass spectral analysis of MHC-eluted peptides and MHC class I tetramer staining of patient T cells suggested putative mCALR neoepitopes were not naturally processed and presented. Finally, we investigated whether ectopic expression of arginine recycling enzymes argininosuccinate synthetase (ASS) and/or ornithine transcarbamylase (OTC) in CAR T cells endows resistance to immunosuppression driven by arginine depletion. Increased ASS/OTC expression and function was detected in CAR-engineered T cells, however enhanced cytotoxicity and proliferation of CAR T cells was not observed following arginine depletion.
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Supervisor: | Not available | Sponsor: | Not available | ||||
Qualification Name: | Thesis (Ph.D.) | Qualification Level: | Doctoral | ||||
EThOS ID: | uk.bl.ethos.723386 | DOI: | Not available | ||||
Keywords: | QH426 Genetics ; QR180 Immunology ; RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||
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