UTILIUM · Unraveling The Immune Landscape In Uveal Melanoma
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-09-01 → 2020-08-31
- EU contribution
- €200,195
- Participants
- 1
- Scheme
- MSCA-IF-EF-SE
Lines connect the coordinator with its partners.
Results in brief
Unraveling The Immune Landscape In Uveal Melanoma
Cancer Immunotherapy is the newest approach in the fight against cancer. The overall aim is to activate the patient’s own immune system against tumor cells. In previous decades, research in Cancer Immunotherapy did not provide significant breakthroughs in the clinic. However, the recent introduction of immune checkpoint inhibitors (ICI) led to a revolution in cancer treatment. ICI are antibodies releasing the brakes from the immune system (e.g. anti-PD1, anti-CTLA4) and were first shown to have survival benefit in cutaneous melanoma patients. The astonishing results gave rise to many clinical trials and ICI proved to be effective in multiple tumor types. Despite great successes of Cancer Immunotherapy, striking differences in objective tumor responses to immunotherapies are observed both within and between tumor types. Multiple tumor types appear to be non-responsive to ICI in clinical trials. Even in tumor types with shared cellular origin, like uveal and cutaneous melanoma, responses to ICI could not be further apart; response rates in cutaneous melanoma reach up to 60%, while in uveal melanoma (UM) they do not exceed 5%. The aim of my project was to use multiple approaches to unravel the immune landscape in UM, including RNA sequencing and spectroscopic imaging, focussing both on the tumor cells and immune cells. Among others, analyses revealed immune checkpoint expression and immune cell subset presence within the tumor microenvironment. Culture of tumor-infiltrating lymphocytes to be tested for tumor reactivity in autologous models was impeded by the very small tumor biopsies leading to an adjusted approach with fresh tissue analysis obtaining extended data on the immune landscape in primary UM. These data can be used for the development of data-based-hypothesis to overcome immune escape mechanisms specific for UM. In addition, clinical data of approximately 100 patients with metastatic UM were analyzed, showing a low but clinically relevant response rate to combined ICI. These results, together with a second publication from a different research group, impacted the current choice of treatment in patients with metastatic UM in multiple countries.
Data: CORDIS, © European Union
Project objective
Cancer Immunotherapy is the latest breakthrough in the fight against cancer, especially with the successes of checkpoint inhibitors. However, numerous tumors appear non-responsive, including uveal melanoma (UM) despite its shared cellular origin with cutaneous melanoma. In this project, I propose to study the immune landscape of UM and explore strategies to overcome mechanisms detrimental to the antitumor immune response. I will employ highly innovative technologies from the fields of genomics, immunology and bioinformatics to explore the tumor microenvironment. Gene expression profiles of UM metastases and neoantigen presentation will be obtained by RNA sequencing. The functional expression of multiple immune markers will be analyzed by cutting-edge multispectral immunohistochemistry to determine immune cell subset presence in a qualitative and quantitative manner. The obtained knowledge will subsequently be used to test and improve reactivity of tumor-infiltrating lymphocytes in an autologous model. These experiments require optimal expansion of tumor-infiltrating T cells, which is highly developed at the laboratory of prof. Svane at the Center for Cancer Immune Therapy at the Herlev Hospital in Copenhagen, Denmark. I expect that this project will provide a more complete overview of the immune landscape of UM and reveal important mechanisms underlying immune suppression in UM. The findings of this project could pave the way to the clinical development of successful immunotherapeutic strategies for the treatment of UM and potentially other tumor types resistant to immune checkpoint inhibitors. Finally, this project will improve my laboratory and leadership skills, greatly improving my chances of achieving the next goal in my career: a permanent position as an Medical Oncologist with my own lab-based group in the expanding field of Cancer Immunotherapy to accelerate the application of translational research into the clinic.
Original text from CORDIS.
Participants
- REGION HOVEDSTADEN · HillerodCoordinatorDenmark
Links
Data: CORDIS, © European Union