Arbeitsgruppe PD Dr. J. Hassel

Uveal melanoma (UM) is a relatively rare tumor, with just 5 or 6 cases per million people per year. However, it is the most common primary eye tumor and becomes deadliest when it spreads to other parts of the body, especially to the liver. Immunotherapies like immune checkpoint inhibitors (ICIs) are of limited success for metastatic uveal melanoma (mUM). In January 2022, for the first time, the US Food and Drug Administration approved tebentafusp (KIMMTRAK) for mUM treatment. Tebentafusp improved mUM patients' survival; However, only about 50 percent of patients who are positive for the HLA-A*02:01 gene are eligible for the treatment, and tumor response rates are low. Hence, further research is required to investigate potential UM targets that induce tumor death and stimulate anti-tumor immune responses. 

In this regard, cMET, a tyrosine kinase receptor that is highly expressed in uveal melanomas and involved in liver metastasis of UM, could be promising. We aim to investigate the potential of cMET inhibitors, especially for their ability to increase anti-tumor immune responses to boost immunotherapy efficacy; possibly leading to new immunotherapeutic combinatorial approaches for mUM patients in the future.

Funding: Hiege-Stiftung Research Grant

Immunotherapies targeting the immune checkpoints CTLA-4 and PD-1 greatly improved survival of melanoma patients. In addition, the antibody relatlimab, which targets the immune checkpoint LAG-3 was clinically approved in 2022 in combination with nivolumab (αPD-1) for treatment of unresectable metastatic melanoma. However, only a subset of patients responds to immune checkpoint blockade. Investigating the role of newly emerging immune checkpoints as LAG-3 and TIM-3 and the factors that influence immunotherapy response are thus important tasks for research.

While most studies focus on LAG-3 and TIM-3 expression on immune cells, our group observed expression of LAG-3 and TIM-3 in tumour cells of melanoma metastases. We aim to investigate melanoma cell intrinsic LAG-3 and TIM-3 expression using various methods, correlate this data with clinical data and study the functional role of LAG-3 expression in melanoma cells using in vitro model systems.

Immunotherapies targeting the immune checkpoints CTLA-4 and PD-1 greatly improved survival of melanoma patients. In addition, the antibody relatlimab, which targets the immune checkpoint LAG-3 was clinically approved in 2022 in combination with nivolumab (αPD-1) for treatment of unresectable metastatic melanoma. However, only a subset of patients responds to immune checkpoint blockade. Investigating the role of newly emerging immune checkpoints as LAG-3 and TIM-3 and the factors that influence immunotherapy response are thus important tasks for research.

While most studies focus on LAG-3 and TIM-3 expression on immune cells, our group observed expression of LAG-3 and TIM-3 in tumour cells of melanoma metastases. We aim to investigate melanoma cell intrinsic LAG-3 and TIM-3 expression using various methods, correlate this data with clinical data and study the functional role of LAG-3 expression in melanoma cells using in vitro model systems.

Funding: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project number 259332240 / RTG 2099 and a scientific grant from BMS

Ipilimumab is a CTLA-4 antibody which blocks downregulation of activated T cells and is successfully used to treat patients with metastasized melanoma. However, its activity in the brain is limited to small asymptomatic lesions and hence it is routinely combined with radiation of brain metastases. It is believed that the release of tumor antigens by radiation might enhance response to immune checkpoint blockers but not much is known on the mechanisms.

In cooperation with P. Beckhove, Regensburg we aim to detect differences in the peripheral blood between patients who receive either stereotactic (1-3 brain metastases) or whole brain radiotherapy (WBRT, > 3 brain metastases) depending on the treatment schedule either starting with radiation or with immunotherapy (see study design).

Primary endpoint: immunological and imaging response at 3 months after completion of radiation in the different treatment arms

Immunologic investigations include FACS analysis for T cell composition, IFN-gamma Elispot analysis of separated CD4 and CD8 T cells for reactivity against 5 major melanoma associated antigens and detection of tumor antigen specific Treg

Funding: Bristol Myers Squibb, Research Grant
Staff: I. Hülsmeyer, BTA

Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers, and these T-cell fractions can also be effectively used in the context of TIL therapy, which involves the harvest, ex vivo expansion and reinfusion of autologous TIL.

In the frame of the BMBF-Junior consortium TIL-REP we aim to investigate:

1. Identification of biomarkers for clinical response through immunohistochemical analysis of TIL before and during treatment with immune checkpoint blockers
2. Identification of tumor-reactive TILs and their use as biomarkers through TCR repertoire profiling of the TIL and PBMC compartments before and during treatment
3. Enabling TIL therapy in our clinic through optimization of TIL isolation and expansion

These studies should not only help to identify biomarkers for response, but are crucial to find out if a combination of TIL infusion and treatment with immune checkpoint blockers might be useful. These data will be used to eventually plan a phase 1 trial combining TIL treatment with immune checkpoint blockers.

http://www.sys-med.de/de/nachwuchsforschung/juniorverbuende/til-rep/tp-4/

Funding: BMBF Research Grant
Staff: J. Roth, BTA; J. Winkler/C. Bender, rotating residents

STAT5 is a transcription factor involved in signal transduction pathways inducing anti-apoptotis and proliferation. From previous investigations in the fish melanoma model of Xiphophorus maculatus it is known that STAT5 plays a crucial role in cell survival and proliferation of melanoma cells (Morcinek et al, 2002; Wellbrock et al, 2005; Hassel et al, 2008).

Interferon-alpha is used adjuvant to treat patients with stage II/III melanoma. Besides the influence on the immune system e.g. by upregulation of MHC class I and II molecules and activation of macrophages interferons have a direct anti-oncogenic effect in vitro. Here, interferon receptors induce growth inhibition in melanoma cells via activation of STAT1. Mutation of STAT1 is known to cause melanoma resistance. In interferon resistant melanoma cell lines we found a high expression of STAT5 and a low expression of STAT1. Hence, this might be a hint for interferon resistance, but nothing is known if this plays a role in vivo.

The aim of this project is to evaluate STAT1,3 and 5 expression in melanoma metastasis by immunohistochemistry and evaluate activation of the transcription factors by the use of phophos-antibodies in immunofluorescence staining. Results will be correlate dot the clinical course.

Funding: Department funds
Staff: J. Roth, BTA; J. Winkler, rotating resident

In the last years new treatment options emerged for patients with metastatic melanoma. These include targeted treatments with BRAF and MEK inhibitors as well as the immune checkpoint blockers Ipilimumab and the PD-1 antibodies. And there are many other antibodies and small molecules in pipeline tested in early clinical trials. Hence, there will be many possibilities to combine drugs or for sequential schedules, e.g. for the combination of targeted and immunotherapies.

In an ex vivo system where 300µm thick tissue slices from melanoma metastases will be taken into culture we aim to test substances on their effect on tumor cells, e.g. the expression of PD-L1.

Funding: Department funds
Staff: J. Roth, BTA; N. Lang

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  Stefanie Friese
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  Jasmin Roth

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  Devayani Machiraju
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  Melanie Wiecken