A combined treatment using multimodal anti-tumor approaches, including immunotherapy and the blocking of signaling pathways, will very likely provide improved possibilities to attack tumor cells. However, parallel to increasing the efficacy of anti-tumor treatment it is crucial to control for adverse effects in order to avoid major drawbacks in clinical trials.
Adverse effects might occur as a result of a potent anti-tumor immune response, affecting organs such as lungs and liver (e.g. following cytokine immunotherapy), or they might result following targeted inhibition of a specific signaling pathway that dysfunctions in tumors (e.g. inhibitors of epidermal growth factor receptor in epithelial tumors or MEKK inhibitors in melanoma leading to severe cutaneous side effects). Both types of side effects limit the dose and/or duration of the treatment, thus jeopardizing successful treatment of the tumor. Knowledge on the mechanisms of these effects will allow us to establish strategies to avoid or dampen them.
Moreover, combined treatments might help reduce such unwanted effects while showing much improved anti-tumor properties. The early stage clinical testing of ipilimumab (an antibody to Cytotoxic TLymphocyte Antigen 4, CTLA-4) plus the B-Raf kinase inhibitor vemurafenib and the use of interleukin 2/antiinterleukin 2 antibody complexes are some examples of innovative multimodal early clinical trials ready to be tested in patients (investigator-initiated trials).
In focusing on the translation of basic research discoveries to clinical testing and back, this URPP aims at assessing and improving the beneficial effects of novel single or combined treatment strategies and simultaneously minimizing the adverse effects.
Our specific aims are:
1. Assessment of efficacy and adverse effects of novel single or combined treatment strategies using relevant (humanized) pre-clinical animal models.
2. Realization of novel investigator-initiated phase I/II clinical trials using lead (combination) regimens.
3. Investigation of the signaling pathways involved during serious adverse effects to established and novel treatment strategies.