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.

Ethical approval was obtained to take fresh tumor tissue biopsies in melanoma patients. The original plan was to include 40 patients, 20 patients with rare melanoma subtypes and 20 patients with cutaneous melanoma. An amendment was written to include another 40 patients from which a biopsy of the primary UM could be taken. At the end of my fellowship 65 evaluable patients were included. The TILs and tumor cell lines cultured from the cutaneous melanoma patients are incorporated in a large meta-analyses (Gokuldass, submitted) and are used in multiple project from PhD students at CCIT. For the UM part, we aim to include 6 more patients (expected to be finish in December 2020) to complete our cohort of 40 primary UM with information on the immune landscape. I also obtained ethical approval to use stored tumor tissue from previously treated patients with rare melanoma subtypes. To select a cohort of patients with metastatic UM I analyzed the Danish Metastatic Melanoma database. I analyzed the real-world outcomes of treatment with immune checkpoint inhibitors and chemotherapy in unselected patients with metastatic UM in a nationwide, population-based study in Denmark. We observed a partial response to first-line treatment in 7% of patients treated with anti-PD-1 monotherapy and in 21% with combined anti-CTLA-4 plus anti-PD-1 therapy. After the introduction of first-line treatment with immune checkpoint inhibitors, the estimated 1-year overall survival rate increased from 25.0% to 41.9% and the median overall survival improved from 7.8 months to 10.0 months. Overall, the introduction of immune checkpoint inhibitors as first-line treatment appears to have significantly improved the real-world survival of patients with metastatic UM, despite relatively low response rates compared to cutaneous melanoma. With the lack of therapies proven effective in randomized trials, these data support the treatment with combined immune checkpoint inhibitors in patients with metastatic UM. These results were published in 2019 (Bol et al, Cancers 2019) and presented at multiple conferences including the ESMO annual meeting 2019 and the DMG annual meeting 2020. The results were discussed in a broader context in a published review on melanoma of the ocular region (Bol et al, IJMS 2020). Results of the analyses of the immune landscape on the stored tumor tissue are ongoing and expected to be published in 2021.

The real-world data of combined immune checkpoint inhibition in metastatic UM already impacted the preferred choice of treatment in Denmark. In addition, the results, together with similar real-world data from Germany, changed the view om combined immune checkpoint inhibition in these patients in the Netherlands leading to more centers treating these patients with immunotherapy. Furthermore, I expect the upcoming results of the project to give further insight in the immune landscape of uveal melanoma which will further augment the search for new treatments options for metastatic UM patients, currently desperate for effective treatment

Periodic Reporting for period 1 - UTILIUM (Unraveling The Immune Landscape In Uveal Melanoma)

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