Developing combination therapy to improve viral vector cancer vaccine efficacy
The development of effective cancer immunotherapies presents several major challenges that must be considered. Notably, it requires the generation of specific immune responses against cancer cells whilst counteracting the highly immunosuppressive mechanisms of the tumour microenvironment. Vaccinatio...
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| Format: | Thesis |
| Language: | English |
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2023
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| _version_ | 1811139786162831360 |
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| author | Noblecourt, L |
| author2 | van Den Eynde, B |
| author_facet | van Den Eynde, B Noblecourt, L |
| author_sort | Noblecourt, L |
| collection | OXFORD |
| description | The development of effective cancer immunotherapies presents several major challenges that must be considered. Notably, it requires the generation of specific immune responses against cancer cells whilst counteracting the highly immunosuppressive mechanisms of the tumour microenvironment. Vaccination strategies consisting of heterologous prime/boost with recombinant chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) has been shown to induce high magnitude of specific cytotoxic CD8+ T cell responses against cancer antigens. Despite these specific anti-tumour immune responses, in therapeutic pre-clinical studies, ChAdOx1/MVA vaccination has shown limited tumour control. Undeniably, it is necessary to develop treatment combination strategies to overcome the multitude of mechanisms that cancer cells use to escape the immune system. However, to successfully combine therapies and generate synergy, research is needed to comprehend their respective therapeutic mechanisms, and determine the optimal sequence of treatment administration. In this study, we tested a novel combination of three treatments comprising of ChAdOx1/MVA vaccines, a chemotherapy regimen based on Carboplatin and Paclitaxel (CarboTaxol) and anti-programmed cell death protein-1 (PD1) therapy. We discovered that this triple combination therapy exhibited strong therapeutic effects in murine tumour models, outperforming corresponding double- treatment combinations. Importantly, we demonstrated that, at a specific therapeutic window, CarboTaxol increased the magnitude of the specific CD8+ T cell response induced by ChAdOx1/MVA. We explored the mechanisms behind the adjuvant effect of CarboTaxol and discovered that this chemotherapy induced T cell factor 1 (TCF1) in CD8+ T cells in both mouse models and human samples. Lastly, we showed the importance of the timing of anti-PD1 administration, relative to vaccination, and established that CarboTaxol allowed more flexibility for anti-PD1 administration. This study brings into light new roles for CarboTaxol and holds promises for testing this combination strategy in clinical trials. |
| first_indexed | 2024-09-25T04:11:37Z |
| format | Thesis |
| id | oxford-uuid:149f135d-35ea-47dc-acd4-3578de560c79 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:11:37Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:149f135d-35ea-47dc-acd4-3578de560c792024-06-26T10:33:57ZDeveloping combination therapy to improve viral vector cancer vaccine efficacyThesishttp://purl.org/coar/resource_type/c_db06uuid:149f135d-35ea-47dc-acd4-3578de560c79Cancer--ImmunotherapyEnglishHyrax Deposit2023Noblecourt, Lvan Den Eynde, BLeung, CThe development of effective cancer immunotherapies presents several major challenges that must be considered. Notably, it requires the generation of specific immune responses against cancer cells whilst counteracting the highly immunosuppressive mechanisms of the tumour microenvironment. Vaccination strategies consisting of heterologous prime/boost with recombinant chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) has been shown to induce high magnitude of specific cytotoxic CD8+ T cell responses against cancer antigens. Despite these specific anti-tumour immune responses, in therapeutic pre-clinical studies, ChAdOx1/MVA vaccination has shown limited tumour control. Undeniably, it is necessary to develop treatment combination strategies to overcome the multitude of mechanisms that cancer cells use to escape the immune system. However, to successfully combine therapies and generate synergy, research is needed to comprehend their respective therapeutic mechanisms, and determine the optimal sequence of treatment administration. In this study, we tested a novel combination of three treatments comprising of ChAdOx1/MVA vaccines, a chemotherapy regimen based on Carboplatin and Paclitaxel (CarboTaxol) and anti-programmed cell death protein-1 (PD1) therapy. We discovered that this triple combination therapy exhibited strong therapeutic effects in murine tumour models, outperforming corresponding double- treatment combinations. Importantly, we demonstrated that, at a specific therapeutic window, CarboTaxol increased the magnitude of the specific CD8+ T cell response induced by ChAdOx1/MVA. We explored the mechanisms behind the adjuvant effect of CarboTaxol and discovered that this chemotherapy induced T cell factor 1 (TCF1) in CD8+ T cells in both mouse models and human samples. Lastly, we showed the importance of the timing of anti-PD1 administration, relative to vaccination, and established that CarboTaxol allowed more flexibility for anti-PD1 administration. This study brings into light new roles for CarboTaxol and holds promises for testing this combination strategy in clinical trials. |
| spellingShingle | Cancer--Immunotherapy Noblecourt, L Developing combination therapy to improve viral vector cancer vaccine efficacy |
| title | Developing combination therapy to improve viral vector cancer vaccine efficacy |
| title_full | Developing combination therapy to improve viral vector cancer vaccine efficacy |
| title_fullStr | Developing combination therapy to improve viral vector cancer vaccine efficacy |
| title_full_unstemmed | Developing combination therapy to improve viral vector cancer vaccine efficacy |
| title_short | Developing combination therapy to improve viral vector cancer vaccine efficacy |
| title_sort | developing combination therapy to improve viral vector cancer vaccine efficacy |
| topic | Cancer--Immunotherapy |
| work_keys_str_mv | AT noblecourtl developingcombinationtherapytoimproveviralvectorcancervaccineefficacy |