Arbeitsgruppe PD Dr. J. Hassel

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

Hypophysitis is a frequent autoimmune side effect in patients treated with ipilimumab. Unfortunately almost none of the affected hypophysis recover despite high dose steroid treatment probably because diagnosis is done too late when hormones already drop in the peripheral blood.

Despite the fact that infiltrating lymphocytes could be found in hypophysitis autopsy samples you can detect antibodies against TSH-producing cells. Hence, we would like to find out if these could be used to early diagnose hypophysitis and early start of anti-inflammatory treatment.
 

Funding: Department funds
Staff: J. Roth, BTA

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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  Jasmin Roth

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  Devayani Machiraju
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  Melanie Wiecken