Developing viral vectored vaccines for MAGE-expressing tumours
The MAGE-type antigen family represent excellent targets for a therapeutic cancer vaccine. However, numerous attempts to develop effective MAGE-targeting cancer vaccines to date have shown poor induction of specific CD8+ T-cell responses and little clinical efficacy. In this study, a novel vaccinati...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2020
|
| Subjects: |
| _version_ | 1826307444311064576 |
|---|---|
| author | McAuliffe, J |
| author2 | Leung, C |
| author_facet | Leung, C McAuliffe, J |
| author_sort | McAuliffe, J |
| collection | OXFORD |
| description | The MAGE-type antigen family represent excellent targets for a therapeutic cancer vaccine. However, numerous attempts to develop effective MAGE-targeting cancer vaccines to date have shown poor induction of specific CD8+ T-cell responses and little clinical efficacy. In this study, a novel vaccination strategy based on a heterologous prime-boost with recombinant Chimpanzee Adenovirus (ChAdOx1) and Modified vaccinia Ankara (MVA) viral vectors was assessed for its potential in targeting MAGE-expressing tumours. The immunogenicity and anti-tumour efficacy of vaccination with ChAdOx1/MVA encoding the murine MAGE-type antigen P1A was evaluated in pre-clinical murine models. Heterologous prime-boost with ChAdOx1/MVA encoding P1A induced a very strong P1A-specific CD8+ T-cell response in DBA/2 and BL/6 mice and demonstrated good therapeutic efficacy in the P1A-expressing 15V4T3 tumour model. Many tumours are poorly infiltrated by tumour-specific CD8+ T-cells, which is believed to underlie the unresponsiveness of many patients to recently developed immunotherapies such as immune checkpoint blockade. Vaccination was seen to greatly increase the magnitude of P1A-specific CD8+ T-cell infiltrate into the tumour and synergised with anti-PD-1 blockade to provide improved control of tumour growth and increased survival. ChAdOx1/MVA vectors encoding the human MAGE-type antigens MAGE-A3 and NY-ESO-1 were also constructed and their immunogenicity evaluated in mice with the view to translation of this strategy to the clinical setting. A prime with ChAdOx1 encoding a dual-antigen MAGE-A3/NY-ESO-1 fusion construct was seen to induce high magnitude CD8+ T-cells to both antigens, which could be boosted further still against either antigen of choice with an MVA vector encoding either MAGE-A3 or NY-ESO-1 alone. Overall, these results strongly indicate that ChAdOx1/MVA is an efficient vaccination strategy for generating MAGE-type antigen-specific CD8+ T-cell responses and that vaccination in combination with PD-1 blockade has high therapeutic potential for treating cancer patients with MAGE-expressing tumours. |
| first_indexed | 2024-03-07T07:03:14Z |
| format | Thesis |
| id | oxford-uuid:6bed3c8f-4a74-4b47-82aa-1bd001eb18fd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:03:14Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:6bed3c8f-4a74-4b47-82aa-1bd001eb18fd2022-03-30T17:08:25ZDeveloping viral vectored vaccines for MAGE-expressing tumoursThesishttp://purl.org/coar/resource_type/c_db06uuid:6bed3c8f-4a74-4b47-82aa-1bd001eb18fdTumour ImmunologyExperimental immunologyCancer ImmunotherapyImmunologyEnglishHyrax Deposit2020McAuliffe, JLeung, CVan den Eynde, BPugh, CThe MAGE-type antigen family represent excellent targets for a therapeutic cancer vaccine. However, numerous attempts to develop effective MAGE-targeting cancer vaccines to date have shown poor induction of specific CD8+ T-cell responses and little clinical efficacy. In this study, a novel vaccination strategy based on a heterologous prime-boost with recombinant Chimpanzee Adenovirus (ChAdOx1) and Modified vaccinia Ankara (MVA) viral vectors was assessed for its potential in targeting MAGE-expressing tumours. The immunogenicity and anti-tumour efficacy of vaccination with ChAdOx1/MVA encoding the murine MAGE-type antigen P1A was evaluated in pre-clinical murine models. Heterologous prime-boost with ChAdOx1/MVA encoding P1A induced a very strong P1A-specific CD8+ T-cell response in DBA/2 and BL/6 mice and demonstrated good therapeutic efficacy in the P1A-expressing 15V4T3 tumour model. Many tumours are poorly infiltrated by tumour-specific CD8+ T-cells, which is believed to underlie the unresponsiveness of many patients to recently developed immunotherapies such as immune checkpoint blockade. Vaccination was seen to greatly increase the magnitude of P1A-specific CD8+ T-cell infiltrate into the tumour and synergised with anti-PD-1 blockade to provide improved control of tumour growth and increased survival. ChAdOx1/MVA vectors encoding the human MAGE-type antigens MAGE-A3 and NY-ESO-1 were also constructed and their immunogenicity evaluated in mice with the view to translation of this strategy to the clinical setting. A prime with ChAdOx1 encoding a dual-antigen MAGE-A3/NY-ESO-1 fusion construct was seen to induce high magnitude CD8+ T-cells to both antigens, which could be boosted further still against either antigen of choice with an MVA vector encoding either MAGE-A3 or NY-ESO-1 alone. Overall, these results strongly indicate that ChAdOx1/MVA is an efficient vaccination strategy for generating MAGE-type antigen-specific CD8+ T-cell responses and that vaccination in combination with PD-1 blockade has high therapeutic potential for treating cancer patients with MAGE-expressing tumours. |
| spellingShingle | Tumour Immunology Experimental immunology Cancer Immunotherapy Immunology McAuliffe, J Developing viral vectored vaccines for MAGE-expressing tumours |
| title | Developing viral vectored vaccines for MAGE-expressing tumours |
| title_full | Developing viral vectored vaccines for MAGE-expressing tumours |
| title_fullStr | Developing viral vectored vaccines for MAGE-expressing tumours |
| title_full_unstemmed | Developing viral vectored vaccines for MAGE-expressing tumours |
| title_short | Developing viral vectored vaccines for MAGE-expressing tumours |
| title_sort | developing viral vectored vaccines for mage expressing tumours |
| topic | Tumour Immunology Experimental immunology Cancer Immunotherapy Immunology |
| work_keys_str_mv | AT mcauliffej developingviralvectoredvaccinesformageexpressingtumours |