Ruprecht-Karls-Universität Heidelberg
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Hassel0119 - Scientist (f/m) / PhD position
Project no:
Hassel0119

Project leader:

Project supervisor:
Hassel, Jessica
Application deadline:
15. Dec 2019
Start of PhD project:
1. Feb 2020

Project description:

Title:
The Role of the immune checkpoints LAG-3 and TIM-3 for Immunotherapy of Melanoma
Summary:
Despite good efficacy of immune checkpoint blocker treatment in metastatic melanoma, many patients still fail to respond to therapies that target CTLA-4 (cytotoxic T-lymphocyte-associated Protein 4) or PD-1 (Programmed cell death protein 1). Our work demonstrates that the intratumoral immune infiltrate plays an important role for responsiveness, i.e. patients showing stronger tumor infiltration by regulatory T cells (Treg) and by PD-1 expressing tumor infiltrating lymphocytes (TIL) seem to benefit more from PD-1 blockage. The role of other immune checkpoints such as LAG-3 (lymphocyte-activation gene 3) and TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) is less clear. In patients with PD-1 antibody (ab) treatment, an increase in LAG-3 mRNA levels was observed intratumorally. Upregulation of TIM-3 expression on TILs was shown to
induce resistance to PD-1 ab treatment. Preliminary immunohistochemical data show that LAG-3 and TIM-3 are not only expressed by infiltrating immune cells in melanoma metastases, but also by melanoma cells as such. Altogether, the role of LAG-3 and TIM-3 in melanoma immunity and immunotherapy is hitherto not sufficiently elucidated. In our project, we aim to investigate how LAG-3 and TIM-3 expressed by immune as well as melanoma cells influence the efficacy of
immune checkpoint blocker treatment. In addition, the role of these immune checkpoints on tumor cells and the role for tumor growth and immune escape will be investigated.
References:
1. Menzer C, Menzies AM, Carlino MS, Reijers I, Groen EJ, Eigentler T, de Groot JWB, van der Veldt AAM, Johnson DB, Meiss F, Schlaak M, Schilling B, Westgeest HM, Gutzmer R, Pföhler C, Meier F, Zimmer L, Suijkerbuijk KPM, Haalck T, Thoms KM, Herbschleb K, Leichsenring J, Menzer A, Kopp-Schneider A, Long GV, Kefford R, Enk A, Blank CU, Hassel JC. Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations.
J Clin Oncol. 2019 Nov 20;37(33):3142-3151.

2. Hassel JC. 5-year results for pembrolizumab treatment of advanced melanoma. Lancet Oncol. 2019 Sep;20(9):1187-1189.

3. Schank TE, Hassel JC. Immunotherapies for the Treatment of Uveal Melanoma-History and Future. Cancers (Basel). 2019 Jul 24;11(8). pii: E1048.

4. Machiraju D, Moll I, Gebhardt C, Sucker A, Buder-Bakhaya K, Schadendorf D, Hassel JC: STAT5 expression
correlates with recurrence and survival in melanoma patients treated with interferon-α. Melanoma Res 28: 204-210, 2018.

5. Anwar H, Sachpekidis C, Winkler J, Kopp-Schneider A, Haberkorn U, Hassel JC*, Dimitrakopoulou-Strauss A*:
Absolute number of new lesions on 18F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab. Eur J Nucl Med Mol Imaging 45: 376-383, 2018.

6. Hassel JC, Jiang H, Bender C, Winkler J, Sevko A, Shevchenko I, Halama N, Dimitrakopoulou-Strauss A, Haefeli WE, Jäger D, Enk A, Utikal J, Umansky V: Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe). Oncoimmunology 6: e1326440, 2017.

7. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S,
Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375: 1845-1855, 2016.

8. Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, Meng M, Fritz D, Vascotto F, Hefesha H, Grunwitz C, Vormehr M, Hüsemann Y, Selmi A, Kuhn AN, Buck J, Derhovanessian E, Rae R, Attig S, Diekmann J, Jabulowsky RA, Heesch S, Hassel J, Langguth P, Grabbe S, Huber C, Türeci Ö, Sahin U. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016 Jun 16;534(7607):396-401.
Methods that will be used:
Flow cytometry, Immunohistology, RT-PCR, Western Blot, cell and tissue culture, proliferation and apoptotic assays
Cooperation partners:
Different collaboration partners at the dkfz (Abdollahi, Poschke, Eichmüller, Offringa, Boutros) and University Hospital Mannheim (Cerwenka, Umansky, Platten). In addition, collaboration with Gustave Roussy Paris (Zitvogel, Eggermont) and Francis Crick Institute London (Turajlic, Larkin).
Personal qualifications:
• Master’s degree in a relevant academic field, or a gedree that allows them to embark in a PhD
• Experience in methods of molecular biology
• Very good english skills
• Independent way of working, capacity for team work, flexibility
Keywords:
melanoma, immunotherapy, immune checkpoints, therapy resistance