Mathematical modelling of T cell infiltration in tumours
Lead Research Organisation:
University of Oxford
Department Name: SABS CDT
Abstract
The complexities of spatially varying biological systems are often not fully captured when constructing non-spatial mathematical models. The aim of this project is to identify the conditions under which different modelling strategies are appropriate for spatially heterogeneous systems, in particular the system of interactions between tumour and immune cells, and ultimately the behaviours of this system under the action of cancer immunotherapy.
T cell infiltration is an important factor in the prognosis of cancer patients and in the outcome of treatments such as immunotherapy. Therefore, development of cancer immunotherapies requires knowledge of, and the ability to predict, the heterogeneous distribution of T cells within the tumour. Previous studies of tumour-immune interactions have used a variety of modelling techniques, including spatio-temporal models such as cellular automata (CA), agent-based models (ABM) and systems of partial differential equations. Other modelling approaches have used systems of ODEs, which are computationally less expensive, but often do not fully capture the spatial aspects of the system modelled. In contrast, spatio-temporal models are computationally expensive, but allow the incorporation of spatial intricacies and, in the case of CA and ABM, allow observations of single cell behaviours.
In this project, spatio-temporal and non-spatial models of tumour-immune interactions will be constructed, and the results of these modelling approaches compared to identify the conditions under which non-spatial models are appropriate to use in this context, and to pinpoint elements of the spatial models which cannot be fully captured by the non-spatial models. The models will then be extended to incorporate the action of cancer immunotherapies, such as T-cell bispecific antibodies, and will be evaluated in their reliability of replicating treatment outcomes. Spatially resolved immunohistochemistry data from tumour biopsies in clinical trials will be used to tune model parameters, to validate the computational representations of the mechanisms of action of immunotherapy molecules under development, and may serve as a basis to analyse the validity of the different modelling approaches. The relationship between the phenomenological parameters in the non-spatial model and the more mechanistically meaningful parameters in the spatial model will also be determined. The modelling strategies developed could be used to investigate how the dose and schedule of cancer immunotherapies drives spatiotemporal changes in the tumour microenvironment.
This research would have the potential to impact on mathematical modelling in many different contexts beyond cancer immunotherapy, by clearly identifying the situations in which non-spatial models are valid in approximating spatially heterogeneous systems.
This project falls within the EPSRC Mathematical Biology research area. Roche is sponsoring this project, and Dr Lucy Hutchinson will be the industrial supervisor from the company.
T cell infiltration is an important factor in the prognosis of cancer patients and in the outcome of treatments such as immunotherapy. Therefore, development of cancer immunotherapies requires knowledge of, and the ability to predict, the heterogeneous distribution of T cells within the tumour. Previous studies of tumour-immune interactions have used a variety of modelling techniques, including spatio-temporal models such as cellular automata (CA), agent-based models (ABM) and systems of partial differential equations. Other modelling approaches have used systems of ODEs, which are computationally less expensive, but often do not fully capture the spatial aspects of the system modelled. In contrast, spatio-temporal models are computationally expensive, but allow the incorporation of spatial intricacies and, in the case of CA and ABM, allow observations of single cell behaviours.
In this project, spatio-temporal and non-spatial models of tumour-immune interactions will be constructed, and the results of these modelling approaches compared to identify the conditions under which non-spatial models are appropriate to use in this context, and to pinpoint elements of the spatial models which cannot be fully captured by the non-spatial models. The models will then be extended to incorporate the action of cancer immunotherapies, such as T-cell bispecific antibodies, and will be evaluated in their reliability of replicating treatment outcomes. Spatially resolved immunohistochemistry data from tumour biopsies in clinical trials will be used to tune model parameters, to validate the computational representations of the mechanisms of action of immunotherapy molecules under development, and may serve as a basis to analyse the validity of the different modelling approaches. The relationship between the phenomenological parameters in the non-spatial model and the more mechanistically meaningful parameters in the spatial model will also be determined. The modelling strategies developed could be used to investigate how the dose and schedule of cancer immunotherapies drives spatiotemporal changes in the tumour microenvironment.
This research would have the potential to impact on mathematical modelling in many different contexts beyond cancer immunotherapy, by clearly identifying the situations in which non-spatial models are valid in approximating spatially heterogeneous systems.
This project falls within the EPSRC Mathematical Biology research area. Roche is sponsoring this project, and Dr Lucy Hutchinson will be the industrial supervisor from the company.
Planned Impact
The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.
The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.
Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners
"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."
New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.
For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,
"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."
However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.
The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students
"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."
To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.
The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.
The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.
Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners
"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."
New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.
For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,
"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."
However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.
The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students
"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."
To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.
The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.
Organisations
People |
ORCID iD |
| Philip Maini (Primary Supervisor) | |
| Roisin Stephens (Student) |