Research interest: Combination of targeted and immunotherapy
Development of inducible murine melanoma models
It is crucial to test new therapeutic approaches in appropriate
in vivo models that simulate the human cancer reality.
Transplantable tumor models often do not mimic the complex
interaction between the tumor cell and the tumor microenvironment
and therefore may have little predictive value for the treatment of
cancer patients. Inducible or spontaneous murine melanoma models
are more physiological, but due to the late onset of tumor
formation less practical for long-term immunotherapeutic
experiments. We have crossed several strains inheriting typical
mutations found in human melanoma to simulate early and late stage
We aim to identify mechanisms of tumor immune escape and to
develop therapeutic protocols to overcome these. Aside other
mechanisms play co-inhibitory molecules a major role in immune
Role of co-inhibitory molecules during tumor immune escape
Appropriate T cell activation depends on TCR ligation and a
positive secondary signal. Recent work revealed that this secondary
signal is not an on-off phenomenon but a signal of modulated
intensity, which is orchestrated by several co-stimulatory and
co-inhibitory molecules. We and others have shown that one of the
ligands (PD-L1) of one such a co-inhibitory molecule (PD-1) is
highly expressed on tumor cells and leads to impaired immune
responses. We found an increased PD-L1 expression on metastases
compared to primary melanoma in human, but no influence on overall
survival, raising the question in which situations PD-L1 inhibits
tumor specific T cells, which is a current project.
Combination of targeted and immunotherapy
While targeted therapies are thought be not toxic for immune
cells, they alter the tumor microenvironment so that increased or
decrease tumor immune infiltration can occur. Understanding
mechanisms of this indirect immune modulation via targeted agents
will provide insights for optimal combinations of these compounds.
In a late stage melanoma mouse model we that that while combination
of BRAF and MEK inhibition improved tumor control, BRAF inhibitors
impaired tumor immune infiltration and did not synergize with T
cell checkpoint blockade by anti-PD-1, -PD-L1 and -CTLA-4 mAb.
Current experiments aim at understanding the mechanism of BRAF
inhibitor-mediated decrease of tumor immune infiltration.
Identification of tools for TIL
Aside the blockade of co-inhibitory molecules, adoptive transfer
of tumor specific T cells has been a promising therapy approach.
However, as with the othert immunotherapies the response percentage
of such a therapy is low and promising results have been observed
so far only in melanoma patients. Therefore we are currently
exploring approaches to improve expansion of tumor infiltrating
lymphocytes (TIL) from renal cell carcinoma (RCC).