The Use of PET/CT for the Tracking of Positron Labelled Cell Therapies to Investigate Cell Distribution and Therapeutic Efficacy in the Diseased Lung

Brief description of the context of the research including potential impact

Cell therapies provide potential treatments for lung cancer and chronic respiratory diseases that that have limited treatment options and poor survival rates. However, the distribution of cells in patients is currently unknown and unpredictable due to the complexity of cell/host interactions. We have validated 89-Zirconium (89Zr)-oxine as a rapid cell label agent for PET/CT in mesenchymal stem cells (MSCs) at clinical doses for their application in 3 patients in an imaging arm of Phase II of the UCL TACTICAL (NCT03298763: fully funded by the MRC and the imaging arm by the JP Moulton Charity Trust). However, 89Zr is not yet widely used in clinical practice and accurate image quantitation of positron-based radiotracers within the lung is challenging. This first-in-man study will be used to establish 89Zr as an clinical cell labelling imaging agent and develop image analysis methods to map the bio-distribution and pharmacokinetics of a genetically-modified stem cell product, providing safety and efficacy data that can be used in the development and optimisation of cell therapies for patients.

Aims and Objectives
-The specific objectives are to:

This project aims to develop image analysis methods to clearly understand 89Zr-labelled cell localization and distribution to provide quantitative measures applicable to both healthy and diseased lung tissue using data acquired from both preclinical and clinical PET/CT systems. Our specific aims are to:

i) To develop the tools needed to accurately track 89Zr radiolabelled cells in pre-clinical studies using PET/CT.

ii) To apply the methods to two different cell types and respiratory diseases to determine if quantitative changes in uptake can characterise the potential lung cell repair caused by cell treatments.

iii) To validate these techniques pre-clinically and to determine the potential of the using radiolabelled cells in humans with lung disease.

iv) To translate these techniques into humans and validate the ability to track radiolabelled MSC-TRAIL in humans.

Novelty of Research Methodology.

89Zr-oxine is a rapid cell labelling technology for PET imaging which we have validated for clinical translation in mesenchymal stem cells (cells) as part of the UCL TACTICAL clinical trial. However, 89Zr is not yet widely used in clinical practice and this will be the first study that has utilized an 89Zr-labelled cell product in human. It is therefore important to ensure that accurate image quantitation 89Zr-labelled cells are developed, validated, and correlated with imaging outcomes of disease progression. As positron-based radiotracers within the lung is challenging the imaging analysis methods obtained will also be of high valuable to the nuclear physics community as a whole.

Alignment to EPSRC's strategies and research areas

Our project is aligned to the "Developing Future Therapies" strategy (Healthcare technologies) by supporting the development of novel cell therapies by using imaging technologies to provide safety and efficacy data thereby reducing risk to patients.

The project also aligns with the following research areas: Medical Imaging (including medical image and vision computing), artificial intelligence technologies, biomaterials and tissue engineering.

Any companies or collaborators involved

GlaxoSmithKline (GSK), Royal Free Hospital (second supervisor Beverley Holman), Prof Sam Janes (leader of TACTICAL trail).

The critical mass of scientists and engineers that i4health will produce will ensure the UK's continued standing as a world-leader in medical imaging and healthcare technology research. In addition to continued academic excellence, they will further support a future culture of industry and entrepreneurship in healthcare technologies driven by highly trained engineers with deep understanding of the key factors involved in delivering effective translatable and marketable technology. They will achieve this through high quality engineering and imaging science, a broad view of other relevant technological areas, the ability to pinpoint clinical gaps and needs, consideration of clinical user requirements, and patient considerations. Our graduates will provide the drive, determination and enthusiasm to build future UK industry in this vital area via start-ups and spin-outs adding to the burgeoning community of healthcare-related SMEs in London and the rest of the UK. The training in entrepreneurship, coupled with the vibrant environment we are developing for this topic via unique linkage of Engineering and Medicine at UCL, is specifically designed to foster such outcomes. These same innovative leaders will bolster the UK's presence in medical multinationals - pharmaceutical companies, scanner manufacturers, etc. - and ensure the UK's competitiveness as a location for future R&D and medical engineering. They will also provide an invaluable source of expertise for the future NHS and other healthcare-delivery services enabling rapid translation and uptake of the latest imaging and healthcare technologies at the clinical front line. The ultimate impact will be on people and patients, both in the UK and internationally, who will benefit from the increased knowledge of health and disease, as well as better treatment and healthcare management provided by the future technologies our trainees will produce.

In addition to impact in healthcare research, development, and capability, the CDT will have major impact on the students we will attract and train. We will provide our talented cohorts of students with the skills required to lead academic research in this area, to lead industrial development and to make a significant impact as advocates of the science and engineering of their discipline. The i4health CDT's combination of the highest academic standards of research with excellent in-depth training in core skills will mean that our cohorts of students will be in great demand placing them in a powerful position to sculpt their own careers, have major impact within our discipline, while influencing the international mindset and direction. Strong evidence demonstrates this in our existing cohorts of students through high levels of conference podium talks in the most prestigious venues in our field, conference prizes, high impact publications in both engineering, clinical, and general science journals, as well as post-PhD fellowships and career progression. The content and training innovations we propose in i4health will ensure this continues and expands over the next decade.