Development of a protocol to study novel radiotherapy-immunotherapy combinations in pre-clinical models of locally advanced rectal cancer

Gillespie, Michael A. (2024) Development of a protocol to study novel radiotherapy-immunotherapy combinations in pre-clinical models of locally advanced rectal cancer. PhD thesis, University of Glasgow.

Abstract

Heterogeneous responses to neo-adjuvant chemoradiotherapy are observed in Locally Advanced Rectal Cancer (LARC). Understanding the molecular and immunological factors underpinning response to radiotherapy-based treatment strategies may promote the development of novel treatment strategies to overcome resistance mechanisms and improve response rates. Murine models of LARC and experimental platforms to deliver precise radiotherapy to small animals, will enable the pre-clinical testing and development of radiotherapy and immunotherapy combinations to guide future clinical trials.

Despite numerous technological advances in pre-clinical modelling of CRC, models which recapitulate the anatomy and mutational composition of LARC have been lacking. In Chapter 3, I describe the development of a novel orthotopic organoid transplant model which recapitulates histological features of aggressive disease, expresses common driver mutations, and maintains immunocompetence. Furthermore, the described model demonstrates reproducibility, high engraftment and is amenable to high experimental throughput.

In Chapter 4, I then utilise the developed orthotopic model of LARC to demonstrate that precise delivery of clinically relevant fractionated radiotherapy is possible in the pre-clinical setting. I then performed irradiation studies to characterise the effects of single fraction and fractionated radiotherapy to the model developed in thesis. In Chapter 4, I characterise the radio-resistance of the orthotopic model of LARC which has been developed, and identify numerous potential resistance mechanisms.

In Chapter 5, I then show the feasibility of administering fractionated radiotherapy and immunotherapy agents to an orthotopic model of LARC. Improved survival was demonstrated following treatment with fractionated radiotherapy and PD-1 inhibition. Overall, this thesis describes significant advances in the pre-clinical modelling of LARC and experimental capabilities for developing novel radiotherapy and immunotherapy combinations, which hold potential to inform the treatment scheduling of fractionated radiotherapy and PD-1 inhibition.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR180 Immunology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Supervisor's Name: Sansom, Professor Owen and Roxburgh, Professor Campbell
• Date of Award: 2024
• Depositing User: Theses Team
• Unique ID: glathesis:2024-84221
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 Apr 2024 13:27
• Last Modified: 15 Apr 2024 08:50
• Thesis DOI: 10.5525/gla.thesis.84221
• URI: https://theses.gla.ac.uk/id/eprint/84221