Background: MSCTRAIL is a cell-based therapy consisting of human allogeneic umbilical cord-derived MSCs genetically modified to express the anti-cancer protein TRAIL. Though cell-based therapies are typically designed with a target tissue in mind, delivery is rarely assessed due to a lack of translatable non-invasive imaging approaches. In this preclinical study, we demonstrate 89 Zr-oxine labelling and PET-CT imaging as a potential clinical solution for non-invasively tracking MSCTRAIL biodistribution. Future implementation of this technique should improve our understanding of MSCTRAIL during its evaluation as a therapy for metastatic lung adenocarcinoma. Methods: MSCTRAIL were radiolabelled with 89 Zr-oxine and assayed for viability, phenotype, and therapeutic efficacy post-labelling. PET-CT imaging of 89 Zr-oxine-labelled MSCTRAIL was performed in a mouse model of lung cancer following intravenous injection, and biodistribution was confirmed ex vivo. Results: MSCTRAIL retained the therapeutic efficacy and MSC phenotype in vitro at labelling amounts up to and above those required for clinical imaging. The effect of 89 Zr-oxine labelling on cell proliferation rate was amountand time-dependent. PET-CT imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer up to 1 week post-injection, validated by in vivo bioluminescence imaging, autoradiography, and fluorescence imaging on tissue sections. Conclusions: 89 Zr-oxine labelling and PET-CT imaging present a potential method of evaluating the biodistribution of new cell therapies in patients, including MSCTRAIL. This offers to improve understanding of cell therapies, including mechanism of action, migration dynamics, and inter-patient variability.
Routinely, there is a visual basis to nuclear medicine reporting: a reporter subjectively places a patient's condition into one of multiple discrete classes based on what they see. The addition of a quantitative result, such as a standardised uptake value (SUV), would provide a numerical insight into the nature of uptake, delivering greater objectivity, and perhaps improved patient management. For bone scintigraphy in particular quantification could increase the accuracy of diagnosis by helping to differentiate normal from abnormal uptake. Access to quantitative data might also enhance our ability to characterise lesions, stratify and monitor patients' conditions, and perform reliable dosimetry for radionuclide therapies. But is there enough evidence to suggest that we, as a community, should be making more effort to implement quantitative bone SPECT in routine clinical practice? We carried out multiple queries through the PubMed search engine to facilitate a crosssectional review of the current status of bone SPECT quantification. Highly cited papers were assessed in more focus to scrutinise their conclusions. An increasing number of authors are reporting findings in terms of metrics such as SUV max. Although interest in the field in general remains high, the rate of clinical implementation of quantitative bone SPECT remains slow and there is a significant amount of validation required before we get carried away.
PurposeMSCTRAIL is a new stem cell-based therapy for lung cancer, currently in phase I evaluation (ClinicalTrials.gov ref: NCT03298763). Biodistribution of cell therapies is rarely assessed in clinical trials, despite cell delivery to the target site often being critical to presumed mechanism of action. This preclinical study demonstrates that MSCTRAIL biodistribution dynamics can be detected non-invasively using 89Zr-oxine labelling and PET imaging, thus supporting use of this cell tracking technology in phase II evaluation.MethodsMSCTRAIL were radiolabelled with a range of 89Zr-oxine doses, and assayed for cell viability, phenotype and therapeutic efficacy post-labelling. Cell biodistribution was imaged in a mouse model of lung cancer using PET imaging and bioluminescence imaging (BLI) to confirm cell viability and location in vivo up to 1 week post-injection.ResultsMSCTRAIL retained therapeutic efficacy and MSC phenotype at doses up to and above those required for clinical imaging. The effect of 89Zr-oxine labelling on cell proliferation rate was dose and time-dependent. PET imaging showed delivery of MSCTRAIL to the lungs in a mouse model of lung cancer, with PET signal correlating with the presence of viable cells as assessed by bioluminescence imaging, ex vivo autoradiography and matched fluorescence imaging on lung tissue sections. Human dosimetry estimates were produced using simulations and preclinical biodistribution data.Conclusion89Zr-oxine labelling and PET imaging present an attractive method of evaluating the biodistribution of new cell-therapies, such as MSCTRAIL. This offers to improve understanding of mechanism of action, migration dynamics and interpatient variability of MSCTRAIL and other cell-based therapies.
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