Mechanistic modelling to determine the limits of clinical and pre-clinical cancer immunotherapies
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| Title: | Mechanistic modelling to determine the limits of clinical and pre-clinical cancer immunotherapies |
|---|---|
| Authors: | Brown, Liam |
| Committee Members: | Gaffney, Eamonn; Coles, Mark |
| Summary: | Immune-mediated clearance of a tumour is predicated on successful activation, migration and engagement of cytotoxic CD8+ T-cells. There are numerous factors that may impede these processes and that vary considerably between patients. In this thesis, I describe the use of mechanistic models to quantify and identify mechanisms that limit immune responses and immunotherapeutics against tumours. I describe the use of a model of T-cell activation in the lymph node to quantify the impact of patient and vaccine-specific variables on short peptide vaccination success. The model is used to simulate a virtual clinical trial, with predicted patient responses consistent with IMA901, a clinical trial of a short peptide vaccination in renal cell carcinoma patients. This leads to the conclusion that the limited efficacy of IMA901 could be due to the short peptide off-rates, and to suggestions that could have improved IMA901's results. I then describe an ODE model of T-cell trafficking through the bloodstream to quantify the maximum delivery rate of bioengineered T-cells to healthy tissue and tumours in different organs and species, and how these rates scale between species. Predicted absolute delivery rates of T-cells in mice are found to be much larger than equivalent rates in humans. This could explain why pre-clinical success of bioengineered T-cells in solid tumours has not translated to the clinic as it has for haematological cancers. Finally, this model is extended with PDEs to quantify the persistence of T-cells within organs and fit to lymphocyte localisation data in the rat. The advantages over the use of ODEs for describing T-cell localisation are discussed along with potential and planned future work. I close by discussing results in an immuno-oncological context, and the extent to which mouse, mathematical and mechanistic models are representative or useful in human medicine. |
| URL: | https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.786105 |
| Database: | OpenDissertations |
| FullText | Text: Availability: 0 |
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| Header | DbId: ddu DbLabel: OpenDissertations An: ddu.oai.ethos.bl.uk.786105 AccessLevel: 6 PubType: Dissertation/ Thesis PubTypeId: dissertation PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Mechanistic modelling to determine the limits of clinical and pre-clinical cancer immunotherapies – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Brown%2C+Liam%22">Brown, Liam</searchLink> – Name: Author Label: Committee Members Group: Au Data: <searchLink fieldCode="CO" term="%22Gaffney%2C+Eamonn%22">Gaffney, Eamonn</searchLink>; <searchLink fieldCode="CO" term="%22Coles%2C+Mark%22">Coles, Mark</searchLink> – Name: Abstract Label: Summary Group: Ab Data: Immune-mediated clearance of a tumour is predicated on successful activation, migration and engagement of cytotoxic CD8+ T-cells. There are numerous factors that may impede these processes and that vary considerably between patients. In this thesis, I describe the use of mechanistic models to quantify and identify mechanisms that limit immune responses and immunotherapeutics against tumours. I describe the use of a model of T-cell activation in the lymph node to quantify the impact of patient and vaccine-specific variables on short peptide vaccination success. The model is used to simulate a virtual clinical trial, with predicted patient responses consistent with IMA901, a clinical trial of a short peptide vaccination in renal cell carcinoma patients. This leads to the conclusion that the limited efficacy of IMA901 could be due to the short peptide off-rates, and to suggestions that could have improved IMA901's results. I then describe an ODE model of T-cell trafficking through the bloodstream to quantify the maximum delivery rate of bioengineered T-cells to healthy tissue and tumours in different organs and species, and how these rates scale between species. Predicted absolute delivery rates of T-cells in mice are found to be much larger than equivalent rates in humans. This could explain why pre-clinical success of bioengineered T-cells in solid tumours has not translated to the clinic as it has for haematological cancers. Finally, this model is extended with PDEs to quantify the persistence of T-cells within organs and fit to lymphocyte localisation data in the rat. The advantages over the use of ODEs for describing T-cell localisation are discussed along with potential and planned future work. I close by discussing results in an immuno-oncological context, and the extent to which mouse, mathematical and mechanistic models are representative or useful in human medicine. – Name: URL Label: URL Group: URL Data: <link linkTarget="URL" linkTerm="https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.786105" linkWindow="_blank">https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.786105</link> |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=ddu&AN=ddu.oai.ethos.bl.uk.786105 |
| RecordInfo | BibRecord: BibEntity: Languages: – Code: eng Text: English Subjects: – SubjectFull: 616.99 Type: general – SubjectFull: Cancer--Mathematical models ; Mathematical Biology ; Immunology--Mathematical models Type: general Titles: – TitleFull: Mechanistic modelling to determine the limits of clinical and pre-clinical cancer immunotherapies Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Brown, Liam IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 01 Type: published Y: 2018 |
| ResultId | 1 |
