Development of Cytomegalovirus-Based Vectors in CancerVaccination
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
Cancer accounts for ~13% of deaths worldwide. Immune cells, specifically T-cells, are exciting therapeutic targets in the control of cancer (http://goo.gl/8esLLb). Cytomegalovirus (CMV) vaccine vectors are unique in their ability to induce large multi-functional T-cell responses, with up to 20% of T-cells targeted against a single protein, and have yielded unprecedented control of infection in preclinical HIV vaccination studies.
We will harness the unique properties of CMV vectors to induce anti-cancer T cell responses. HIV CMV-based vaccines have used live replicating virus. CMV is a pathogen and such constructs will not be permitted in human trials, but non-replicating vectors induce inferior immune response. To address this issue, we (Stanton/Humphreys) developed a vector in which CMV replication occurs only in the presence of doxycycline (dox), a non-toxic antibiotic. The vector can be administered with dox, will replicate and induce a strong immune response. When dox is removed, the vector is killed. This project will develop these unique vectors and harness exciting immune-modulatory strategies to induce robust and protective T cell responses against cancer.
(i) Determine optimal dox administration strategies. The student will determine how long dox-dependent vectors must replicate for in vivo (in mice) to enable induction of strong anti-cancer immune responses and assess how efficiently the vector is lost following dox withdrawal. Vectors will also be grown in human cells using dox concentrations/timings as defined in mice, and used to stimulate autologous T cells using systems developed in the Wooldridge lab, thus identifying vector immunogenicity in humans.
(ii) Determining and optimising vector-induced anti-tumour protection. We will test vectors expressing the 5T4 cancer protein, and examine vector-induced protection from tumours expressing 5T4 protein, using tumour models established in lab (in collaboration with Awen Gallimore, Cardiff). The Humphreys lab has identified numerous immune pathways that promote CMV-induced T cell responses. These pathways will be induced during immunization with CMV-dox vectors, and the impact on vector immunogenicity and anti-tumour protection will be measured.
(iii) Investigate the ability of Adenovirus prime-boost regimen to enhance anti-tumour activity. Replication deficient recombinant adenovirus (RAd) vectors are widely used viral vectors in clinical trials. We have shown that a prime-boost regimen using CMV and RAd generates a far greater/rapid immune response than either vector alone. The ability of the replication controllable CMV and RAd to synergise to induce 5T4-specific immune responses and tumour control will be assessed in vivo.
We will harness the unique properties of CMV vectors to induce anti-cancer T cell responses. HIV CMV-based vaccines have used live replicating virus. CMV is a pathogen and such constructs will not be permitted in human trials, but non-replicating vectors induce inferior immune response. To address this issue, we (Stanton/Humphreys) developed a vector in which CMV replication occurs only in the presence of doxycycline (dox), a non-toxic antibiotic. The vector can be administered with dox, will replicate and induce a strong immune response. When dox is removed, the vector is killed. This project will develop these unique vectors and harness exciting immune-modulatory strategies to induce robust and protective T cell responses against cancer.
(i) Determine optimal dox administration strategies. The student will determine how long dox-dependent vectors must replicate for in vivo (in mice) to enable induction of strong anti-cancer immune responses and assess how efficiently the vector is lost following dox withdrawal. Vectors will also be grown in human cells using dox concentrations/timings as defined in mice, and used to stimulate autologous T cells using systems developed in the Wooldridge lab, thus identifying vector immunogenicity in humans.
(ii) Determining and optimising vector-induced anti-tumour protection. We will test vectors expressing the 5T4 cancer protein, and examine vector-induced protection from tumours expressing 5T4 protein, using tumour models established in lab (in collaboration with Awen Gallimore, Cardiff). The Humphreys lab has identified numerous immune pathways that promote CMV-induced T cell responses. These pathways will be induced during immunization with CMV-dox vectors, and the impact on vector immunogenicity and anti-tumour protection will be measured.
(iii) Investigate the ability of Adenovirus prime-boost regimen to enhance anti-tumour activity. Replication deficient recombinant adenovirus (RAd) vectors are widely used viral vectors in clinical trials. We have shown that a prime-boost regimen using CMV and RAd generates a far greater/rapid immune response than either vector alone. The ability of the replication controllable CMV and RAd to synergise to induce 5T4-specific immune responses and tumour control will be assessed in vivo.
Organisations
People |
ORCID iD |
| Ian Humphreys (Primary Supervisor) | |
| Marta Williams (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013794/1 | 01/10/2016 | 30/09/2025 | |||
| 1943693 | Studentship | MR/N013794/1 | 01/10/2017 | 24/07/2022 | Marta Williams |
| Description | Lab-based teaching medical students |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Undergraduate students |
| Results and Impact | Practical Research Experience for first year medical students. It is important that future doctors understand the research process and are able to evaluate research evidence presented during training and in future careers as practicing clinicians. This research module enables students to demonstrate their ability to conduct a small scientific project, showing rigour in following a scientific method, data collection, analysis and reporting of their data. Students attend an introductory session where they are provided with background information on my research area including details on the scientific methods and associated clinical relevance. Students complete one practical session in small teams with an opportunity to undertake and observe the methods first-hand. Students are then required to prepare and give a 15-minute team presentation for assessment (8 minute talk with 5 minutes questions and 2 minutes for peer review) for which I conduct a separate session, where they can review their findings and ask any final questions. |
| Year(s) Of Engagement Activity | 2019,2020 |
| Description | Science in Health event |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | 80 pupils attended for a day at a research hospital, to raise interest in STEM subjects and careers in research. |
| Year(s) Of Engagement Activity | 2018,2019 |
| Description | Teaching primary school pupils |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | Presentation and workshops for primary school pupils, to raise their knowledge of viral infections, immune system and the importance of research. |
| Year(s) Of Engagement Activity | 2019,2020 |