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MEDICIS-produced radioisotope beams for medicine

Periodic Reporting for period 2 - MEDICIS-PROMED (MEDICIS-produced radioisotope beams for medicine)

Reporting period: 2017-04-01 to 2019-03-31

Ovarian cancer is presently the second deadliest form of cancer amongst women and has poor prognosis, despite significant research efforts in that domain. The most current cure combines chemotherapy and surgery. Often the pathology is diagnosed at an advanced stage of the disease. This type of cancer is then difficult to treat with external radiotherapy, because of possible presence of metastasis and because this organ is difficult to irradiate without collateral damages. New treatments are therefore highly needed.
New treatments using isotope pairs have this potential, and is named "theranostics". The field of molecular oncology and nuclear medicine is rapidly evolving. Indeed this personalised medicine approach combines diagnosis by imaging - using PET/CT scanners - and subsequent treatment with a similar radiopharmaceutical for which the imaging isotope is replaced by a treatment isotope.
In the recent years, PET/CT functional imaging using FDG - a glucose analog with an isotope which gives contrast in PET imaging - has had a significant impact on how the patients were managed during their treatment. Alongside the recent marketing of new drugs exploiting new radioisotopes and radioactivity such as Xofigo® and Luthatera® have shown important results to cure other forms of advanced cancers. This field is expected to further expand rapidly and provide new types of treatments combining personalized treatment and its imaging companion with the same radiopharmaceutical and different types of isotopes, emitting positron or gamma light for imaging on one side, and Auger electron, beta and alpha radiation for treatment on the other side.
In addition, isotopes such as 11Carbon can "personalize" hadron therapy treatments by imaging the dose distribution of the implanted ions in European radiotherapy facilities using Carbon treatment such as the CNAO, Centro Nationale de e Oncologia near Milano and Medaustron near Vienna.

MEDICIS-PROMED has significantly advanced the use of radioisotopes for personalized medicine in Europe. This was achieved in three interconnected Work-Packages, with 11 Early Stage Researchers hired by the beneficiaries and 4 recruited in Swiss partner organizations.
A new marker of ovarian cancer has recently been identified and can now be used as a possible target for diagnosis and treatment. It is the TEM1/endosialin protein. An antibody was shown to specifically target this marker in preclinical imaging studies in animal models; this now opens the route for investigations of personalized treatments combining functional imaging and either alpha-emitting or beta-emitting isotopes.
This domain has rapidly progressed on a European level thanks to the present training network proposal where leading academic, medical institutes and high-tech companies have contributed to a multidisciplinary coordinated program. This has build on the new CERN-MEDICIS medical radioisotope beams facility that can produce unique batches of innovative isotopes, such as 149Terbium.
The program has developped along three R&D work packages integrating multidisciplinary intersectorial training teams:
• Development of new radioisotopes and techniques using isotope mass separation for medicine and based on CERN-MEDICIS
• Development and test of 11Carbon PET-aided hadron therapy
• Synthesis & tests of radiopharmaceuticals to diagnose & treat ovarian cancer

Besides the development and tests of the first graphene-coated isotope production targets providing corrosion resistance by Ms. Nazarova trained in the group of Prof Kostya Novozelov, a new type of materials suited for the production of PET (positron-emitting isotopes) imaging ions in a next generation of radiotherapy centers has been patented at Katholik University Leuven. This development is one of the different contributions collected in a dedicated MEDICIS-Promed Technical Design Report written 2 young researchers (ESRs) and 5 contributors from 5 institutes, and coordinated by Dr. Liviu Penescu (Abstract Landscapes) invited in the network to achieve this task.
A notable highlight was the start of the new facility MEDICIS at CERN, which led to a press release during its inauguration that reached 10’s Millions people in general media such as the Forbes online edition. The facility is dedicated to the production of non-conventional isotopes, such as 149-152-155Terbium part of a theranostics (therapy & diagnostics) quadruplet that are proposed for both diagnostics and treatment pharmaceuticals. To date, these isotopes have been made available for preclinical tests. MEDICIS is based on dedicated infrastructures to perform production and physical mass separation of medical isotopes, and on a network of collaborating institutes such as the high flux reactor ILL, the high-power cyclotron Arronax, radiopharmaceutical/chemistry groups at NPL, PSI and IST, hospitals of Lemanic Arc. Our young researchers as central part of the network have addressed European ministers and decision makers. At this occasion, the first proof-of-concept was developed in Lausanne Hospital by Dr Cicone and coworkers, who used an injectable drug tagged with an isotope that can be imaged with PET-CT and that can be used with antibodies for targeted therapies, a fast-growing field for new cancer treatments. It was also presented at the European Association of Nuclear Medicine annual congress in 2017 & 2018 and published in the CERN Courier, distributed in accelerator and physics centers across the world.
CERN-MEDICIS operation culminated with new laser systems for isotope production by V. Gadelshin and a world-first production of a new grade of the therapeutic 169Erbium by R. Formento from Advanced Accelerator Applications (AAA)/Novartis and collaborators, which allows the exploitation of this isotope used only for radiosynovectomy (small joints arthrosis treatment) into the field of theranostics (combination of 2 drugs, a targeted treatment, and its imaging companion).
These results, and others, were exposed during the final conference of MEDICIS-Promed in the medieval village of Erice, that brought together world renown oncologists and scientists, from across Europe, Japan, USA and Canada, as well as representatives from international associations and organizations, SME’s and capital venturists to exchange on the latest results and launch new ideas, in the related field of targeted radiotherapy and techniques for radioisotopes.
The MEDICIS-Promed network has shown to be able to provide a seed for structuring the community with some of the young researchers already employed in the pharmaceutical industry while others continue in clinical or academic research. The final conference served to launch a kick-off meeting to form a network of relevant European medical isotope production centers for this starting research community, as a new version of the national isotope program in USA.
First PET imaging done with a anti-TEM1 bioconjugate and 152Tb innovative isotope
MEDICIS-Promed public lecture on theranostics/personalized medicine by Dr. Buono, former AAA CEO
Nobel Prize winner Novozelov lecturing on Graphene
Robot used in the newly build MEDICIS facility in the CERN Courier magazine
Press release at the start-up of CERN-MEDICIS facility
Presentation of MEDICIS-Promed by one young researcher to state secretary, Belgium
Young researchers at the network training at National Graphene Institute with prof Novozelov
Brainstorming with ESR that kicked of a Technical Design report on future facility using 11Carbon
New radio-isotope transport container Colibri-B and recently graduated Dr. Maietta at Lemer-Pax
Prof. Langevin-Joliot, Granddaughter of Marie Curie that discovered radioactivity, with ESRs
Final conference at the Marojana center in Erice
Schematic of the new bioconjugate functions synthesized in MEDICIS-Promed