Systematic screening of cytotoxic agents targeting oncogenic signaling pathways for combinatorial immunotherapy in tumor models
Daniel Baumann1,2, Caroline Vent1, Nicolas Gengenbacher3, Hellmut Augustin3, Rienk Offringa1,2 1Department of Molecular Oncology of Gastrointestinal Tumors, DKFZ; 2University Clinic, Heidelberg, Germany,3Vascular Oncology and Metastasis Research, DKFZ Heidelberg, Germany
Combinations of immunostimulatory compounds and cytostatic agents are currently being extensively tested against different tumor types. Clearly synergistic anti-tumor responses are rare, however. Furthermore the impact of the compounds on the immune cells itself is insufficiently understood, as is the risk of unanticipated side effects of combination regimens. Therefore, our aim is to study combinatorial immunotherapeutic approaches in a systematic fashion by making use of robust in vitro and in vivo immune cell assays.
In order to select the most effective and immune response potentiating compounds, we are currently screening cytotoxic/cytostatic compounds, such as chemotherapeutic agents and small molecule inhibitors against MAPK or PI3K/AKT signaling for their efficacy against murine and human tumors cell lines and their effects on T cell proliferation and effector functions.
In tumor experiments combination of selected MEK inhibitors with an agonist CD40 antibody show T-cell dependent synergy in different syngeneic transplantable tumor models. In more advanced models, such as the autochthonous BRaf-driven model for metastatic melanoma, the effect is much less prominent, presumably due to a strongly immune suppressive tumor microenvironment and the lack of mutated neoantigens. In order to optimize our models with respect to prediction of clinical outcome, we are developing electroporation-based autochthonous tumor models, which are equipped with immunogenic foreign antigens and can be used to study the metastatic disease.
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