Development of 89Zirconium-PET Tracers for Immune Cell Imaging

The use of cell-based therapies as a living drug have gained considerable attention for the treatment of a range of conditions such as genetic diseases, autoimmune disorders and cancer. The emergence of genetically engineered T cells expressing chimeric antigen receptors (CAR T-cells), together with modulations of immune checkpoints have brought the rapidly advancing field of immunotherapy into a new, revolutionary spotlight with a renewed interest in cell-based therapies. In vivo imaging and tracking of cells can be used to non-invasively improve the accuracy, efficacy and safety of novel immune-modulatory treatments and cell therapies. Positron Emission Tomography (PET) is a powerful non-invasive imaging technique that can be utilised for spatial and longitudinal tracking of different cell types. The long half-life PET isotope zirconium-89 (t1/2 = 78.4 h) has become increasingly available and [89Zr]Zr-Oxine has recently emerged as a promising candidate for direct cell labelling and longitudinal cell tracking. However, the water insolubility and synthesis method of [89Zr]Zr-Oxine may limit its implementation as a routine clinical imaging tool and little work has been performed looking at alternatives to this compound. The aim of this thesis was to investigate alternative approaches and methods for the direct labelling of cells using zirconium-89. This work also describes the first use of zirconium-89 in Cambridge and the set-up of the infrastructure and methods. First, the sensitivity of detecting 89Zr-labelled cells on clinical PET systems was investigated that can inform on the minimal cellular radioactivity needed for detection in prospective clinical studies. Secondly, a peptide-based approach was developed whereby cell penetrating peptides were tested for 89Zr-labelling, purification, quality control and their in vitro properties. 89Zr-labelled peptides were subsequently employed for direct cell labelling in comparison to [89Zr]Zr-Oxine in preparation for preclinical studies.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Lechermann, Laura

Advisor dc:contributor.advisor

• Gallagher, Ferdia

• Zirconium-89
• Cell Tracking
• Positron Emission Tomography
• Direct Cell Labelling

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-2742-6269
0000-0003-4784-5230

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/333705