Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.748796
Title: Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment
Author: Freedman, Joshua
ISNI:       0000 0004 7232 3044
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Abstract:
Oncolytic viruses exploit the cancer cell phenotype to complete their lytic life cycle, releasing progeny virus to infect nearby cells and repeat the process. We modified the oncolytic group B adenovirus EnAdenotucirev (EnAd) to express bispecific single chain antibodies, secreted from infected tumour cells into the microenvironment. The bispecific T cell engager (BiTE) binds to a selected antigen on target cells and crosslinks them to CD3 on T cells, leading to clustering and activation of both CD4 and CD8 T cells. BiTE transcription can be controlled by the virus major late promoter, limiting expression to cancer cells that are permissive for virus replication. We first exemplified this approach using a BiTE that recognises EpCAM, which is highly expressed on many carcinomas and is recently identified as a marker of cancer-initiating cells. A second BiTE was engineered to target FAP on cancer-associated fibroblasts, demonstrating the power of such an approach in targeting cancer-promoting stromal cells of the tumour microenvironment. This strategy can potentiate the cytotoxicity of EnAd and we show using primary pleural effusions, peritoneal malignant ascites and solid prostate tumour specimens that infection of cancer cells with the BiTE-expressing EnAd leads to activation of endogenous T cells to kill endogenous tumour cells or fibroblasts despite the immunosuppressive environment. In this way, we have armed EnAd to combine both direct oncolysis and T cell-mediated killing, yielding a potent therapeutic that should be readily transferred into the clinic.
Supervisor: Seymour, Leonard ; Ashfield, Rebecca Sponsor: Medical Research Council ; Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.748796  DOI: Not available
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