Partner: Mediso Medical Imaging Systems
3rd Supervisor: Tim Witney
Radionuclide-based theranostics, where targeted diagnostic and therapeutic radiopharmaceuticals are combined for the precision treatment of cancer, has revolutionised the field of nuclear medicine. Despite its rapid growth, theranostic applications are in their infancy and will benefit from accurate quantification of radionuclide uptake and post radionuclide therapy dosimetry. Currently, only relative quantification is routinely performed, which comes with numerous limitations in defining representative image-based metrics. Accurate knowledge of activity concentrations across different organs and consequently, the regional distribution of absorbed radiation dose (dosimetry) would aid both translation of theranostic agents and their safe personalised implementation into the clinic. Absolute quantification using advanced SPECT/CT systems, however, can accurately measure radiopharmaceutical concentrations across an in vivo biodistribution by accurately incorporating the system physical characteristics and the imaging physics. Whilst initially only possible for 99mTc-labelled radiopharmaceuticals, absolute quantification has now expanded to other isotopes such as Lutetium-177 (177Lu), Indium-111 (111In), Actinium-225 (225Ac) and Iodine-123 (123I).
These isotopes have recently received considerable attention as theranostic agents, both within KCL, where a number of such radio-labelled agents are developed and explored for theranostic applications and beyond. Absolute quantification with SPECT/CT could potentially aid assessment of disease burden and therapy response in tumours (prediction of therapeutic efficacy and requirement for multiple therapies). In addition, one of the key objectives of quantitative SPECT/CT is to improve dose estimations to critical organs to optimize radionuclide therapy dose administration to achieve the highest delivered tumour dose while limiting potential toxicity (dose to critical organs). Accurate dosimetry is critical in preclinical theranostics in order to interpret radiobiological dose-response relationships and to translate results into clinical applications. Accurate knowledge of the dosimetric profile of a new theranostic agent can accelerate its transltion into a field that, as shown recently by the impact of 68Ga-/177Lu-PSMA into clinical treatment of prostate cancer, has potential for rapid growth.
In this PhD project, the imaging capability and performance of a state-of-the-art preclinical SPECT/CT multipinhole collimator imager will be investigated for theranostic applications using radioisotopes such as 131I, 188Re, 212Pb, 225Ac, etc. Further improvements in absolute quantification using radioisotopes that are challenging to image will be explored through the use of precise voxel-based dosimetry with GATE Monte Carlo simulation.
Specific goals will focus on:
- Performance evaluation of nanoScan SPECT/CT using an innovative high energy multipinhole collimator in combination with theranostics isotopes.
- Identifying factors that compromise quantitative accuracy.
- Analysing and improving the SPECT imaging chain, including calibrations, corrections, acquisition, and reconstruction schemes.
- Developing voxel-based dosimetry, for example through GATE Monte Carlo simulation, using quantitative preclinical SPECT/CT images and possible comparison to organ-defined dosimetry approaches.
- Exploring data reduction methodologies to time sequences in order to simplify data collection and reduce the number of time points required to provide radiopharmaceutical residence times.
The above, at early stages, will most likely involve the use and construction of test objects and the design of suitable experiments and data analysis regimes. Various system parameters can be identified and explored to determine their impact to quantification and consequently, image-based dosimetric estimates. These, among others, include collimator characteristics, energy window settings, image reconstruction parameters, scatter ad attenuation corrections etc At a later stage, aspects with key impact to outcomes can be pursued and developed into data correction and data analysis methodologies. These may extend to experimental study design; For example, developing protocols such as for single time point dosimetry in order to achieve acceptable dosimetry outcomes without the need of extensive repeat imaging. Determining sources of errors and levels of accuracy will also be important for future theranostic applications.
These innovative methodologies will subsequently be applied to a range of novel cancer radionuclide theranostic applications being developed at King’s. Specifically, the various groups within the college are involved with the use of radionuclide imaging for Molecular Imaging such as noninvasive assessment of multiple components of tumour microenvironment in advanced models of cancer, cell tracking, imaging therapy-induced oxidative stress, as well as a toolbox of MI probes modified with alpha, beta and Auger electron-emitters to create novel precision treatments. A range of therapeutic radionuclides and companion imaging partners (in parentheses) are being employed: 225Ac, 213Bi, 227Th, 212Pb (203Pb), 211At (124I), 177Lu (68Ga), 188Re/186Re (99mTc), 67Cu (64Cu), 123I, 67Ga and 201Tl. SPECT imaging will be used to dynamically track the whole body and tissue-specific distribution of relevant therapeutic radionuclides.
As there is potentially a multitude of applications benefiting from methodologies developed as part of the PhD project, we propose a preclinical research champion, Dr Tim Witney (ICAB, BMEIS) working closely with the supervisory team to specifically provide guidance and support on pre-clinical applications in order to maximise the impact of methodologies for quantification and dosimetry. For example, we are developing novel theranostics that target drug-resistant lung cancer, employing a range of advanced animal models, from patient-derived tumours to genetically-engineered animal models. This programme will benefit from the methodologies being developed here.
The PhD research will span across experimental design, data acquisition, image reconstruction and analysis, simulation studies, and development of new calibration approaches; Comprehensive training in any of these elements will be provided through close collaboration with Mediso and at King’s. In addition, as the supervisory team have strong links with the clinical teams at GSTT (one of the largest radionuclide imaging & therapy services in the UK and Europe) involved with clinical theranostics in molecular radiotherapy (MRT) such as 68Ga-/177Lu-Dotatate and 68Ga-/177Lu-PSMA etc, cross-fertilisation of ideas and practices applicable to a clinical context will be sought. It should be noted that the School of Biomedical Engineering and the pre-clinical imaging facility (due to be upgraded to the current state-of-the-art SPECT/CT and PET/CT platform in Spring 2023) are co-located within the Guy’s & St Thomas’ hospital buildings, which should further aid access and exchange with a wider perspective of applications within the field.
The project will offer ample opportunity for integration and interaction with the college research groups who form the key users of preclinical radionuclide imaging and the industry partner offering unique perspectives in pre-clinical and clinical theranostic related technologies, practices and product development.