Cornelissen, Bart

Nonnekens, Julie

Terry, Samantha

English

Molecular radiotherapy (MRT) is a relatively novel anti-cancer treatment option utilising radiolabelled, tumour-specific vectors. Upon binding of these vectors to cancer cells, radioactive decay induces DNA damage and other effects, leading to cancer cell death. Treatment, e.g. [177Lu]Lu-octreotate for neuroendocrine tumours and [177Lu]Lu-PSMA for prostate cancer, are now being implemented in routine clinical practice around the world. Nonetheless, research into their underlying radiobiological effects is essential to further improve current treatment or formulate new ones. The purpose of the European Working Group on the Radiobiology of Molecular Radiotherapy is to promote knowledge, investment, and networking in this area. This report summarises recent research and insights presented at the second International Workshop on Radiobiology of Molecular Radiotherapy, held in London, UK, on March 13 and 14, 2023. The symposium was organised by members of the CRUK RadNet City of London and the European Working Group on the Radiobiology of Molecular Radiotherapy

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Second Symposium of the European Working Group on the Radiobiology of Molecular RadiotherapyJulie Nonnekens, PhD1,2, Bart Cornelissen, PhD3,4, Samantha YA Terry, PhD5, on behalf of the European Working Group on the Radiobiology of Molecular Radiotherapy1 Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands;2 Department of Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.3 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, The Netherlands;4 Department of Oncology, University of Oxford, UK;5 Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King’s College London, UK;First author: Dr Julie Nonnekens, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands. Email: j.nonnekens@erasmusmc.nl Corresponding author: Dr Samantha Terry, School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, UK. Email: samantha.terry@kcl.ac.uk AbstractMolecular radiotherapy (MRT) is a relatively novel anti-cancer treatment option utilising radiolabelled, tumour-specific vectors. Upon binding of these vectors to cancer cells, radioactive decay induces DNA damage and other effects, leading to cancer cell death. Treatment, e.g. [177Lu]Lu-octreotate for neuroendocrine tumours and [177Lu]Lu-PSMA for prostate cancer, are now being implemented in routine clinical practice around the world. Nonetheless, research into their underlying radiobiological effects is essential to further improve current treatment or formulate new ones. The purpose of the European Working Group on the Radiobiology of Molecular Radiotherapy is to promote knowledge, investment, and networking in this area. This report summarises recent research and insights presented at the second International Workshop on Radiobiology of Molecular Radiotherapy, held in London, UK, on March 13 and 14, 2023. The symposium was organised by members of the CRUK RadNet City of London and the European Working Group on the Radiobiology of Molecular Radiotherapy.This second workshop (a hybrid meeting) was a follow-on from the ‘Call to arms editorial article’ published in 2019 (1) and the inaugural meeting in 2021 in Montpellier (2). The aim of this workshop was to update the community on the current state of the art and research on radiobiology in the field of MRT, to be inspired by research performed in the field of external beam radiotherapy and cancer biology and to network with dedicated times in the schedule. In total, 120 attendees (100 live and 20 online) from 11 countries participated in talks, debates, and poster sessions. Proffered talks, posters, and poster pitches were selected from more than 40 abstracts.Jonathan Wadsley from the University of Sheffield, UK, gave the first keynote lecture, highlighting the state of the art of MRT, and indicated where efforts are best invested for impactful clinical success. He started with an overview of current clinical indications of MRT such as 131I for thyroid cancer, 223Ra for prostate cancer bone metastases, radioembolization and the above mentioned [177Lu]Lu-octreotate and [177Lu]Lu-PSMA. Future work, he proposed, should focus on novel tumour indications, novel radionuclides, and combination treatments. He discussed six gaps in our current knowledge, indicating the challenges in standardized dosimetry, and poorly understood radiobiology: 1) How do we personalize therapy to ensure that each patient receives the most effective absorbed dose to treat their tumour whilst maintaining safety and not damaging organs at risk; 2) What absorbed doses are being delivered and what is the radiobiological significance of dose-rate effects?; 3) What are the radiobiological consequences of different types of emissions, with different energies and path lengths?; 4) How do we manage tumour heterogeneity?; 5) What is the role of radiosensitisers?; 6) What can be the effect of immune interactions on therapeutic efficacy? Jonathan also discussed some lessons learned from clinical trials (e.g. SELIMETRY trial) and where we as a community could best lay our efforts to achieve impactful clinical success. This could be focussing on personalising treatment to ensure that every patient gets the maximum possible benefit out of the activity delivered. To perform rigorous, multidisciplinary clinical trials addressing meaningful clinical questions such as dosimetry, radiobiology and molecular biomarkers.A series of proffered talks highlighted the best scored abstracts that had been submitted. Simone Kleinendorst (Radboudumc, Nijmegen, The Netherlands) discussed the potential of combining carbonic anhydrase IX-targeted lutetium-177 treatment with immune checkpoints inhibitors. Hanna Berglund (Uppsala University, Sweden) talked about how p53 stabilization potentiates [177Lu]Lu-octreotate therapy in neuroblastoma. Jordan Cheng (King’s College London, UK) highlighted the option to use chemotherapeutics targeting replication to enhance [177Lu]Lu-octreotate therapy in vitro.	The second session focussed on the role of the tumour microenvironment (TME) and immune response in MRT efficacy. The first talk was an invited lecture by Julie Constanzo from the Montpellier Cancer Research Institute IRCM, France, on the topic of MRT and vesicle signalling in the context of anti-cancer immunity. She showed how the TME plays a major role in the cellular response to radiotherapy (including MRT). MRT acts via induction of targeted effects (such as direct DNA breaks) and non-targeted effects (such as via excretion of cytokines, extracellular vesicles (EVs), DAMPS or chemokines). The latter will lead to direct killing of surrounding cells or activation of immune system. Furthermore, her work showed that membrane targeting with radionuclides can activate the cGAS-STING pathway. She also showed that EVs play a role in enhancing the therapeutic effect via the immune system, since EVs isolated from MRT-treated cells can effectively be used to treat immune competent xenografted mice, but not immunodeficient mice. Future work will focus on the combination of MRT with immune checkpoint inhibitors and when to use this combination. What would, for example, be the best treatment schedule and which patients would be eligible?The session was continued with proffered talks of submitted abstracts. Yasmine Bouden (University of Montpellier, France) gave a talk on the role of double-stranded DNA contained in EVs released by irradiated cells. Gemma Dias (University of Oxford, UK) talked about her work on the anti-tumour immune response induced by [177Lu]Lu-PSMA, and Sapna Lunj (University of Manchester, UK) showed her data on the systemic immune response induced by MRT in men with prostate cancer. The session was followed with poster pitches from the highest ranked poster abstracts. Concluding the first day, participants were divided into groups and were asked to discuss 4 questions and upload their answers in Padlet: 1) My research in radionuclide therapy would progress if I could just…? 2) The next big thing should be…? 3) Other suggestions on how to progress the field? 4) How will we fund this? All answers were compiled and discussed during an audience-engaged discussion on day 2.The second day started with an invited talk by Isabel Pires from The University of Manchester, UK, who gave an extensive overview of how to target hypoxia biology as a radiosensitizing approach in breast cancer. Years of research by many groups has shown that hypoxia causes resistance to radiotherapy, as well as increased genomic instability, increased metastatic potential, metabolic and angiogenic switches, and stemness. Isabel discussed her work on WSB-1, an E3 ligase associated with hypoxia signalling. WSB-1 is a HIF1 target and has a positive feedback loop with HIF1. High expression of WSB-1 is associated with poor prognosis (distant metastasis free survival) for hormone receptor negative breast cancer patients, and downregulation leads to decreased angiogenic and metastatic capacity in vitro and in vivo. More recent data indicates that WSB-1 could regulate the DNA damage response, which gives opportunities for combination treatment strategies. She concluded with the statement that WSB-1 could be a potential novel breast cancer gene biomarker for dysfunctional DNA damage response in hypoxic breast cancer. Similarly detailed radiobiological studies should be on the horizon for MRT.During the audience-engaged discussion, outcomes of the group discussion of the first day were debated. The participants see various promising developments both in the lab and clinic, including novel treatment options such as drug combinations, and the use of Auger electron-emitters. In addition, more emphasis should be put on radiogenomics, dosimetry and novel models such as 3D spheroids and animals. Furthermore, it is essential to include radiobiology and dosimetry in clinical practice, e.g. to enable biomarker research, and to develop quick and easy functional tests for patient selection and prediction of therapy efficacy. The audience showed a clear consensus on standardisation of terminology (e.g. what is this therapy called? Molecular radionuclide therapy, radiopharmaceutical therapy, or targeted radionuclide therapy, etc). It is also essential to better report on experimental procedures and use appropriate controls to allow for standardisation and increase reproducibility. Additionally, there is a great need for better interaction and knowledge exchange within the community. The working group is currently working on follow up on these points.The second keynote talk was held by Fran Balkwill of the Queen Mary University of London, UK. She talked about how the tumour microenvironment, TME, might influence MRT success. Cancers are not just masses of malignant cells but complex organs, to which many other cells are recruited and are sometimes corrupted by the transformed cells. Interactions between those cells create the TME, which can vastly differ between different tumour types. Fran showed their work on high grade serous ovarian cancer which often metastases to the omentum. Mouse models can be used to study this tumour type and its response to treatment since there are many common elements between mouse and human samples, e.g. type of infiltrated immune cells. Her work showed that chemotherapy can stimulate the immune response and modulate the TME and to study this change, it is essential to obtain pre- and post-treatment samples. Very recent work showed live imaging of human tissue slices and co-cultures of different types of cells to follow tumour- and immune cell movement using antibodies.The last 2 sessions of the conference were comprised by the last proffered talks. Paula Raposinho and Ana Belchior (both from the Technical University of Lisbon, Portugal) talked about cellular studies using 67Ga/177Lu-labeled nanoparticles for theranostics of glioblastoma and dosimetric challenges from nanoscopic patterns to biological effectiveness, respectively. Emmanuel Deshayes (Montpellier Cancer Research Institute IRCM, France) gave a lecture on the dose-effect relationship in tumours and healthy organs for patients treated with [177Lu]Lu-DOTA-octreotate. The last 2 talks both focussed on drug screens to find novel combination treatments. Edward O’Neill (University of Oxford, UK) used a clonogenic-based drug screen to identify CDK4/6-inhibitors as potential radiosensitizers for lutetium-177-based MRT and Thom Reuvers (Erasmus University Medical Center Rotterdam, The Netherlands) performed a plate reader-based high-throughput screen and identified DNA-PKcs inhibitors as potent radiosensitizers of [177Lu]Lu-DOTA-octreotate.Many congratulations to Simone Kleinendorst (1st place), Thom Reuvers and Sapna Lunj (joint 2nd place) who were awarded prizes for best oral presentation, and Isabella Strobel (1st place), Anthony Waked and Katarina Gleisner (joint 2nd place) who won the best poster category.Radiobiology of MRT is gaining much attention and various studies are showing the important role for clinical MRT implementation and symposia such as this are highly effective opportunities for networking and establishing novel collaborations. Although growing, the field is not yet overcrowded; in fact, we would go as far as to state that researching the biological mechanisms that influence radionuclide therapy effectiveness would make an excellent research niche for many early career researchers, young and more established academics to move into. At the workshop follow-up meetings were also planned to identify concrete ways forward for the working group. Equally, the Scholar-in-Training (SIT) committee will now be reinstated to increase the visibility of SIT members within the radiobiology of MRT community and works to offer networking and community opportunities. As a community, several recommendations were made to help move the field of molecular radionuclide therapy forward at a faster pace, including standardising the name of MRT to aid visibility amongst other research areas, sharing protocols, collaborating more, and standardisation of reporting on results. Additional information is available at: www.mrtradiobiology.com.AcknowledgmentsThe symposium was generously sponsored by Artios, AstraZeneca, Mediso, MiLabs, RPS Service, and Viewpoint Molecular Targeting (now Perspective Therapeutics). This symposium was also supported by the Radiation Research Unit at the Cancer Research UK City of London Centre [C7893/A28990]. The local organization organising committee included Hafiza Bibi, Vittorio de Santis, Jordan Cheng, and Samantha Terry. The scientific committee included Jordan Cheng, Paul Gape, and Mark Gaze, Jane Sosabowski, Bart Cornelissen, Julie Nonnekens, and Samantha Terry. We thank all panel members, chairs and others who helped make the symposium a success. DisclosureNo potential conflicts of interest relevant to this article exist.Key pointsQuestion: This symposium set out to enable a networking opportunity for biological researchers working in molecular radionuclide therapy and ascertain how we as a group should best proceed.Pertinent Findings: Several suggestions were made to help move the field of molecular radionuclide therapy forward at a faster pace, including creating a scientist-in-training committee, sharing protocols, collaborating more, and standardisation of reporting on results.Implications for Patient Care: By moving the field of molecular radionuclide therapy forward through new connections and more in-depth biological research, further highly effective therapeutic options will become available for patients.References1.	Terry SYA, Nonnekens J, Aerts A, et al. Call to arms: need for radiobiology in molecular radionuclide therapy. Eur J Nucl Med Mol Imaging. 2019;46(8):1588-1590.2.	Cornelissen B, Terry S, Nonnekens J, Pouget JP. European Working Group on the Radiobiology of Molecular R. First Symposium of the European Working Group on the Radiobiology of Molecular Radiotherapy. J Nucl Med. 2021;62(7):14N-15N. 51

Second Symposium of the European Working Group on the Radiobiology of Molecular Radiotherapy

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Second Symposium of the European Working Group on the Radiobiology of Molecular Radiotherapy

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