Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment
<p>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 infe...
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| Other Authors: | |
| Format: | Thesis |
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2017
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| _version_ | 1797074523135148032 |
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| author | Freedman, J |
| author2 | Seymour, L |
| author_facet | Seymour, L Freedman, J |
| author_sort | Freedman, J |
| collection | OXFORD |
| description | <p>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. </p> <p>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.</p> |
| first_indexed | 2024-03-06T23:37:25Z |
| format | Thesis |
| id | oxford-uuid:6e23f1c4-81a1-49e0-8e12-f01d629d61c4 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:37:25Z |
| publishDate | 2017 |
| record_format | dspace |
| spelling | oxford-uuid:6e23f1c4-81a1-49e0-8e12-f01d629d61c42022-03-26T19:22:24ZArming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironmentThesishttp://purl.org/coar/resource_type/c_db06uuid:6e23f1c4-81a1-49e0-8e12-f01d629d61c4ORA Deposit2017Freedman, JSeymour, LAshfield, R<p>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. </p> <p>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.</p> |
| spellingShingle | Freedman, J Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment |
| title | Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment |
| title_full | Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment |
| title_fullStr | Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment |
| title_full_unstemmed | Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment |
| title_short | Arming oncolytic viruses with bispecific T cell engagers (BiTEs) for expression and secretion into the tumour microenvironment |
| title_sort | arming oncolytic viruses with bispecific t cell engagers bites for expression and secretion into the tumour microenvironment |
| work_keys_str_mv | AT freedmanj armingoncolyticviruseswithbispecifictcellengagersbitesforexpressionandsecretionintothetumourmicroenvironment |