Katsiva, Christina; (2025) The Use of PET/CT for the Tracking of Positron Labelled Cell Therapies to Investigate Cell Distribution and Therapeutic Efficacy in the Diseased Lung. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lung cancer is the leading cause of cancer death worldwide with new treatment options urgently needed. Cell therapies can potentially answer this unmet clinical need and improve the life expectancy of lung cancer patients. However, the clinical translation of cell treatments is hindered by the limited knowledge of in vivo distribution of the therapeutic cells in patients. In this work, a clinically translatable direct radiolabelling method of [89Zr]Zr-oxine was developed for a GMP grade mesenchymal stem cell therapy for the treatment of lung cancer. In vitro studies were conducted to assess cell viability and toxicity due to the radiolabelling process. Results showed time and amount of radioactivity dependent sensitivity to [89Zr]Zr-oxine labelling, as well as that the GMP kit formulation used for radiolabelling was non-toxic to the cells. For the application of the radiolabelling method in vivo, an orthotopic mouse model of lung cancer was developed, that represented clear areas of tumour tissue and lung parenchyma, allowing for the clear segmentation of those areas using imaging, for the understanding of the in vivo distribution of the therapeutic cells in the diseased lung. Furthermore, preclinical phantom studies were conducted to assess a preclinical PET/CT system ahead of the in vivo imaging study, identifying the significantly higher noise present in 89Zr imaging studies. The radiolabelling method developed was applied to the orthotopic mouse model of lung cancer, for the longitudinal in vivo tracking of the GMP mesenchymal stem cell therapy using PET/CT imaging. Naïve and tumour bearing mice were utilised and the cells were successfully tracked in vivo up to 7 days post-injection. Quantitative measurements were acquired for different organs with the majority of radioactivity accumulating in the lungs. No differences were identified between tumour bearing and control mice. After the application of corrections a statistically significant difference was identified between lung and tumour, in agreement with the ex vivo measurements conducted, highlighting the importance of applying corrections for the interpretation of imaging findings. Finally, clinical phantoms were acquired to assess the image quality and quantitative accuracy of clinical PET/CT systems for the identification of the optimal imaging protocol that could be applied in clinical cell tracking studies of 89Zr using PET/CT imaging. This thesis, presents a clinically translatable direct radiolabelling method of [89Zr]Zr-oxine for mesenchymal stem cells that can be applied as part of clinical trials, to understand the in vivo distribution of the therapeutic cells using PET/CT imaging, and assess the therapeutic efficacy and possible adverse effects of a stem cell therapy.

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