The development of novel T cell receptor - and chimeric antigen receptor - engineered T cell therapies for the treatment of cancer

Tubb, Vanessa (2017). The development of novel T cell receptor - and chimeric antigen receptor - engineered T cell therapies for the treatment of cancer. University of Birmingham. Ph.D.

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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.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):