Cook AM, Hoang T, Francis R, Nowak AK, Ioppolo J, Mohamed S, Morandeau L.
Funding: Various
Synopsis (lay): Cancer cells can use a surface molecule called PD-L1 to switch off tumour-killing T cells. Antibody drugs called immune checkpoint inhibitors (ICIs) are now commonly given to people with cancer, including mesothelioma, to prevent PD-L1 signalling and stopping the T cells from being switched off; however, the rate of successful response is still considerably less than half.
We know ICIs are generally more effective for people who have more PD-L1 in their tumours, and this can be measured from a biopsy (a small piece of tumour removed surgically). However, we also know that biopsies often do not accurately represent the whole tumour – and that the situation in the tumour can change over time. Since taking repeated biopsies is painful and logistically difficult, we would like to be able to measure PD-L1 levels in the tumour purely by imaging.
In this project we will develop a short-lived radioactive probe that will bind to PD-L1 molecules, allowing us to assess PD-L1 distribution in mouse mesothelioma tumours in live mice using Positron Emission Tomography (PET, a type of medical imaging procedure). We will use this technology to examine how PD-L1 levels change over time, and also in response to different cancer treatments such as chemotherapy, radiotherapy and ICIs.
Results from these experiments will help us to refine how ICIs are given to cancer patients and inform future clinical trials on how to increase the number of people who will respond successfully to treatment.
Synopsis (scientific):
Overall objective: Evaluate the significance of PD-L1 expression in mouse mesothelioma models via PD-L1 PET-CT imaging.
Objective 1: Develop a robust protocol and quality control strategies to produce 89-Zr-anti-PD-L1 radiotracer.
Objective 2: Create an optimal standard operating procedure for PET-CT imaging that and image analysis of mouse mesothelioma tumour using 89-Zr-anti-PD-L1 radiotracer.
Objective 3: Using a model of mouse mesothelioma, perform experiments to investigate how intratumoural PD-L1 expression changes over time in a growing tumour and in response to various cancer therapies.