Periodic Reporting for period 4 - UM Cure 2020 (New therapies for uveal melanoma)
Reporting period: 2020-07-01 to 2021-06-30
The overall goal of the UM Cure 2020 consortium was to combine the efforts of several European Centres of Excellence in clinical ocular oncology and basic research with patient organisations and innovative companies to develop new therapeutic approaches to treat metastatic UM.
We proposed an innovative concept placing the patient central in therapy development. While our major objective was to identify new potential therapeutic strategies for metastatic UM, the centre of our approach was to characterise the tumour tissue from UM patients with metastases, in order to define actionable targets. In addition, we aimed at connecting directly with UM patients throughout Europe, providing them with up-to-date information on new treatments for their disease and possibilities to get involved. Patients were therefore central in each of our research steps up until the dissemination and implementation of the results.
1) We harmonised the collection of UM patient biosamples (primary tumour, liver metastases and matched blood whenever possible) across the 4 reference centres (Institut Curie, University of Liverpool, Leiden University Medical Centre and Jagiellonian University), and set-up a virtual common database registering 235 metastatic UM samples from 165 patients, with matched samples for 51 patients;
2) We have evaluated in vitro in metastasis-derived cell lines over 80 single drugs and their combinations. Pharmacological evaluation of the best in vitro combinations is still ongoing in vivo in patient-derived xenograft (PDX) mouse models of UM metastases, but already allowed to identify one very promising combination;
3) Preclinical models recapitulating the pathophysiology of UM progression and metastases formation were sorely lacking. We have constituted a collection of 36 liver metastasis-derived PDX models, as well as one new metastasis-derived cell line. Genetically-modified models have been established in zebrafish and in mouse and their characterisation is still ongoing, with very interesting first results;
4) Different omics and screening approaches have been performed, with the objective to decipher the genetic alterations and dysregulated signalling pathways in metastatic UM, and the characteristics of the UM immune landscape. We showed that the progression to a metastatic disease is associated with recurrent copy number changes, but with neither additional oncogenic mutation, nor tumour heterogeneity. Although no actionable target came out of NGS analyses, the identification of a subset of tumours characterized by MBD4 inactivation represents an important finding. This event was associated with an outlier response to immunotherapy, but more cases are needed to establish MDB4 as a biomarker of response to immunotherapy. Germline MBD4 mutations also confer a relative risk for UM of almost 10-fold. MBD4 has been added to the clinical gene panel for genetic predisposing conditions in UM at Institut Curie, and also to the tumour prognostication gene panel.
The Curie team also evidenced for the first time the presence of neo-antigens specific to tumour cells and shared between patients, as a result of SF3B1 mutations. Neo-antigen specific T cells can be found both in the blood and in the metastases, which can recognize and kill the tumour cells. Discussions are ongoing for the development of a therapeutic vaccine. Finally, we have been performing a thorough analysis of the immune microenvironment of UM tumours towards the application of other immunotherapy approaches;
5) We have been widely disseminating our project objectives and results in order to increase awareness of the project towards our stakeholders, in particular through the project website (www.umcure2020.org) and social media platforms (Facebook, Twitter and YouTube channel, @UMCURE2020). Our brochure raising awareness on the disease has been widely distributed across Europe through patients, patient advocates and clinicians. Our partner Melanoma Patient Network Europe has been creating an empowered and engaged UM patient community (MPNErare), reaching over 480 members across Europe. These activities will support our ultimate exploitation goal, i.e. the initiation of UM-dedicated clinical trials based on findings described above. Finally, we have been working at the establishment of European Clinical Practice Guidelines for UM, in collaboration with ESMO and the European Reference Network EURACAN; those will be published in 2022.
- Firstly, we have built an unprecedented collection of UM patient samples from primary tumours, metastases, and blood samples across the four reference centres;
- Collected samples have been heavily used under the project, in particular to deliver a deep characterisation of liver metastases at genetic, proteomic, and immunological levels. We have been describing for the first time the genetic landscape of UM metastases, with low heterogeneity apart from a subgroup of patients with MBD4 inactivation that may benefit from immunotherapy. We also evidenced for the first time the presence of neo-antigens specific to tumour cells and shared between patients, as a result of SF3B1 mutations, that open the possibility of therapeutic vaccine development. New actionable target hypotheses obtained through additional approaches are under in vitro validation;
- We have also extended our panel of preclinical models that typify the disease, notably with over 30 mouse PDX models established from liver metastases, and also with genetically-modified models still under full characterisation;
- Many in vitro and in vivo data with single drugs and combinations have been generated. In our last series of in vivo experiments in mouse PDX models, we have uncovered a very promising combination of two drugs that we will now aim at bringing to patients through in a clinical trial.
- European Clinical Practice Guidelines, prepared in collaboration with ESMO and the European Reference Network EURACAN, will be published in 2022 towards a better management of the disease across Europe and further benefits to patients.
Last but not least, patients have been involved in all aspects of our research, in particular through the building of the MPNErare forum, a UM patient community across Europe that has grown tremendously since project start. Increasing knowledge exchange and the empowerment of patients constitutes an important societal impact of the UM Cure 2020 project that we are particularly proud of, beyond the progress made in the characterisation and management of the disease.