Thesis
Optimising pre-clinical in vivo models with CAR T cells for cancer immunotherapy
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2023
- Thesis identifier
- T17543
- Person Identifier (Local)
- 201771655
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Immunotherapy is an active area of oncology research, with Chimeric Antigen Receptor (CAR) T cell therapy showing encouraging results. Significant success has been seen with haematological cancers and there have been recent advances in solid tumours however significant challenges remain, such as overcoming the tumour microenvironment (TME). This project aims to refine pre-clinical in vivo study design and better understand CAR T cells for immunotherapy by investigating different aspects of the process, therefore enhancing translatability and ultimately improving clinical success. Pre-clinical in vivo studies assess CAR T cell treatments in a biological system prior to use in a clinical setting. Standard models cannot be used for CAR T cell therapy as the animal’s competent immune system will reject human cells. We utilised the NSG immunocompromised mouse model, engrafted with human cell lines to evaluate responses to CAR T cell treatment. Although we understand there are limitations to these models, valuable knowledge, applicable to the clinic, can be gained and refining the design of pre-clinical studies. We optimised study design aspects including; consideration of tracking CAR T cells in vivo, evaluating methods to measure subcutaneous tumour volume, optimising CAR T cell dose and initial tumour size to give a statistically relevant response, and optimising cell expansion protocols ex vivo ahead of CAR T cell dosing to understand the biology of the CAR T cell treatment and how this influences therapy success. Our results highlight the importance of a carefully considered study design to optimise the translatability and relevance of in vivo study results. We demonstrated a potential method to track CAR T cells in vivo, using imaging, which would allow further understanding of CAR T cell biodistribution and efficacy. We showed that, for our CAR construct, in mouse in vivo studies there was limited benefit in increasing CAR T cell dose beyond a biology threshold as similar tumour reduction was seen regardless of dose) once this threshold has been passed. Thus, highlighting the value of performing initial pilot studies to optimise study design. Furthermore, we demonstrated that different CAR T cell phenotypes contribute to different profiles for tumour reduction which has implications for refining the CAR T cell product prior to dosing in the clinic. Our findings can be used to refine future in vivo studies and to gain further understanding of the activity and application of CAR T cells in immunotherapy treatments.
- Advisor / supervisor
- Southgate, Thomas
- Plevin, Robin
- Jiang, Hui-Rong
- Resource Type
- Note
- Previously held under moratorium in Chemistry Department (GSK) from 19/10/2023 until 25/11/2025.
- DOI
- Funder
- Embargo Note
关系
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File | 2025-11-26 | 限制运用 |