Periodic Reporting for period 1 - SECURE (Strengthening the European Chain of sUpply for next generation medical RadionuclidEs)
Reporting period: 2022-10-01 to 2024-03-31
The SECURE project aims to contribute to the sustainability of medical isotope production and its safe application in Europe. It focuses on developments in the design of irradiation targets, and production routes for existing and new isotopes for therapy and diagnostics. Isotopes critical to the success of nuclear medicine, such as beta-emitters Cu-64, Ag-111, Lu-177, Tb-161, Re-188 and Au-199 and alpha-emitters Pb-212 and Ac-225 were selected and research activities were identified to address some of the major challenges in securing their future availability, with the objectives:
1. to remove critical barriers along the production of its selected alpha and beta-emitting isotopes that restrict sustainable production,
2. to develop a framework of guidance and recommendations that enable exploring the full clinical potential of alpha and beta particle therapy and its safe application,
3. to provide important lessons learned that act as a demonstration case for addressing issues in upscaling and sustained isotope production.
At present, Ra-223 is the only alpha-emitter radiopharmaceutical which has been granted marketing authorization to treat adults with prostate cancer. This has paved the way for wider use of other alpha emitters such as Ac-225 or Bi-213. The expected demand of nuclear medicine for novel alpha-emitters and beta-emitters requires a re-evaluation of their production methods and inventories of target materials and parent radionuclides.
The SECURE’s consortium goal is to identify and efficiently use the current resources for new radionuclides, in particular for alpha emitters and the relevant beta-emitting theranostic radionuclides. The development of alternative technologies for the production of such therapeutic radionuclides for improved patient treatment requires multidisciplinary scientific and technological knowledge including physics, chemistry, material science, machining of target materials, chemistry, biology and radiobiology, radiopharmacy and nuclear medicine. All this chain of expertise is present in the SECURE consortium.
1. to remove critical barriers along the production of its selected alpha and beta-emitting isotopes that restrict sustainable production,
2. to develop a framework of guidance and recommendations that enable exploring the full clinical potential of alpha and beta particle therapy and its safe application,
3. to provide important lessons learned that act as a demonstration case for addressing issues in upscaling and sustained isotope production.
At present, Ra-223 is the only alpha-emitter radiopharmaceutical which has been granted marketing authorization to treat adults with prostate cancer. This has paved the way for wider use of other alpha emitters such as Ac-225 or Bi-213. The expected demand of nuclear medicine for novel alpha-emitters and beta-emitters requires a re-evaluation of their production methods and inventories of target materials and parent radionuclides.
The SECURE’s consortium goal is to identify and efficiently use the current resources for new radionuclides, in particular for alpha emitters and the relevant beta-emitting theranostic radionuclides. The development of alternative technologies for the production of such therapeutic radionuclides for improved patient treatment requires multidisciplinary scientific and technological knowledge including physics, chemistry, material science, machining of target materials, chemistry, biology and radiobiology, radiopharmacy and nuclear medicine. All this chain of expertise is present in the SECURE consortium.
The demand for therapeutic and diagnostic radionuclides is growing, which motivated the SECURE consortium to work on the developments ensuring their future supply and resolving gaps. The proposed methodologies cover various production aspects of radionuclides for research and sustainable clinical use and were split into parts corresponding to the 4 technical work packages of the project.
The main achievements of WP1 "Target development", can be described by the reported milestones. The experimental work with Ra-226 was initiated and the requirements of Re-226 targets were formulated. Experimental research on target fabrication, encapsulation, irradiation and processing is ongoing. Computational work is done on yield calculations, and the assessment of laboratory practices will be continued. The first deliverable D1.1 Target requirements (quantities and quality) and sourcing for existing and foreseen irradiation infrastructure for the production of alpha-emitting radionuclides was submitted. Specifically, this deliverable has addressed the form of the target relative to the production route specified, namely by proton, deuteron, gamma or neutron irradiation.
Results and activities of WP2 "Production routes" were focused on the techniques for producing alpha-emitters, such as Ac-225 from Ra-226 target, the first experimental tests and Monte Carlo simulations were performed. The production of beta-emitters, such as Tb-161, Au-199 and Ag-111 from Gd-160, Pt-198 and Pd-110 targets, respectively, in nuclear reactors has been investigated through theoretical simulation and experimental tests. The evaluation of the Pb-212 generator developed at NRG has been initiated with a focus on potential clinical applications. Work is underway on preparation for CARP validation with input data discussed with ENEA, and initial conversations started with others including NCBJ. Work was completed on integrating uncertainty parameters into CARP. Promising results were achieved by comparing CARP results to EK gamma spectroscopy and FISPACT calculations. The work will be continued with EK and ENEA data.
WP3 "W-188/Re-188 isotope generator" - Rhenium-188 is a beta-emitter suitable for therapy, it is considered a matching radionuclide to technetium-99m, which is commonly used for diagnostics. However, the use of Re-188 in novel radiopharmaceutical developments is limited. The parent radionuclide W-188 used in W-188/Re-188 can only be produced by irradiating enriched W-186 targets in high-flux reactors. Traditionally, mainly tungsten oxide targets have been used for this purpose, but issues have occurred in the past where some ampoules have been found shattered after irradiation. The mechanism that leads to such ampoule breakage had to be investigated to propose mitigation measures. A feasibility study of W-metal targets was performed by making and dissolving W-metal target samples. Various metal targets were made by pressing, sintering, and cutting W-powder. These studies were supported by analytical and Monte Carlo calculations of neutron self-shielding as a function of sample geometry and density. The W-188/Re-188 generators or Re-188 eluate solutions are now available to the partners of the SECURE project for further quality control testing and radiolabelling experiments.
WP4 "Recommendations for clinical trials and radiation protection" - WP4 concerns the development of recommendations in multiple areas associated with the implementation of radionuclide treatment in clinical practice. These areas include the identification of clinical applications, radiation protection issues in the whole supply chain from radioisotope production up until their administration to a patient, and finally optimised protocols for patient dosimetry evaluation. The produced document "Recommendations on clinical applications of alpha particle therapy" is an exhaustive report of potential clinical applications of new alpha-emitting radionuclides. It concerns sharing insights from the SECURE consortium's experiences and providing recommendations for future clinical trials to establish the therapeutic efficacy of these radionuclides.
The main achievements of WP1 "Target development", can be described by the reported milestones. The experimental work with Ra-226 was initiated and the requirements of Re-226 targets were formulated. Experimental research on target fabrication, encapsulation, irradiation and processing is ongoing. Computational work is done on yield calculations, and the assessment of laboratory practices will be continued. The first deliverable D1.1 Target requirements (quantities and quality) and sourcing for existing and foreseen irradiation infrastructure for the production of alpha-emitting radionuclides was submitted. Specifically, this deliverable has addressed the form of the target relative to the production route specified, namely by proton, deuteron, gamma or neutron irradiation.
Results and activities of WP2 "Production routes" were focused on the techniques for producing alpha-emitters, such as Ac-225 from Ra-226 target, the first experimental tests and Monte Carlo simulations were performed. The production of beta-emitters, such as Tb-161, Au-199 and Ag-111 from Gd-160, Pt-198 and Pd-110 targets, respectively, in nuclear reactors has been investigated through theoretical simulation and experimental tests. The evaluation of the Pb-212 generator developed at NRG has been initiated with a focus on potential clinical applications. Work is underway on preparation for CARP validation with input data discussed with ENEA, and initial conversations started with others including NCBJ. Work was completed on integrating uncertainty parameters into CARP. Promising results were achieved by comparing CARP results to EK gamma spectroscopy and FISPACT calculations. The work will be continued with EK and ENEA data.
WP3 "W-188/Re-188 isotope generator" - Rhenium-188 is a beta-emitter suitable for therapy, it is considered a matching radionuclide to technetium-99m, which is commonly used for diagnostics. However, the use of Re-188 in novel radiopharmaceutical developments is limited. The parent radionuclide W-188 used in W-188/Re-188 can only be produced by irradiating enriched W-186 targets in high-flux reactors. Traditionally, mainly tungsten oxide targets have been used for this purpose, but issues have occurred in the past where some ampoules have been found shattered after irradiation. The mechanism that leads to such ampoule breakage had to be investigated to propose mitigation measures. A feasibility study of W-metal targets was performed by making and dissolving W-metal target samples. Various metal targets were made by pressing, sintering, and cutting W-powder. These studies were supported by analytical and Monte Carlo calculations of neutron self-shielding as a function of sample geometry and density. The W-188/Re-188 generators or Re-188 eluate solutions are now available to the partners of the SECURE project for further quality control testing and radiolabelling experiments.
WP4 "Recommendations for clinical trials and radiation protection" - WP4 concerns the development of recommendations in multiple areas associated with the implementation of radionuclide treatment in clinical practice. These areas include the identification of clinical applications, radiation protection issues in the whole supply chain from radioisotope production up until their administration to a patient, and finally optimised protocols for patient dosimetry evaluation. The produced document "Recommendations on clinical applications of alpha particle therapy" is an exhaustive report of potential clinical applications of new alpha-emitting radionuclides. It concerns sharing insights from the SECURE consortium's experiences and providing recommendations for future clinical trials to establish the therapeutic efficacy of these radionuclides.
All of the work outlined in the different work packages of this proposal will have a long-lasting impact on the field of radionuclide therapy throughout the EU member states. It starts with the research and development of new targets and irradiation protocols for the production of radionuclides used for therapy (both alpha and beta-emitters), securing a safe supply chain that will facilitate an enhancement of existing and new clinical applications. In addition, the safety aspects in the supply chain will include recommendations for the development of personalized planning and patient dosimetry protocols that should enhance in the future the potential of radionuclide therapy as one of the major treatment techniques in cancer.