Summary

Targeted immunotherapy of brain tumors
The central nervous system (CNS) is considered an immune privileged organ, where immune responses are tightly controlled through an intensive cross-talk with the peripheral immune system despite the blood-brain barrier. Despite this tight control autoimmunity takes place in the CNS. A hallmark of intrinsic CNS tumors like gliomas is an active immunosuppression. The cellular and molecular mechanisms that are involved in the deregulation of CNS immunity are incompletely understood but important. We are thus interested in the control of CNS autoimmunity and immune therapeutic approaches to brain tumors.

Specifically we aim at identifying targets for immunotherapy of brain tumors. Using MHC humanized mouse models and patient material we probe mutated proteins for their ability to induce mutation-specific immune responses. To incorporate patient-specificity of such mutated epitopes, we have established a dedicated platform, which allows for identifying patient-specific T cell receptors of neoepitope-specific T cells. At the same time we have exploited shared neoepitopes resulting from driver mutations prevalent in specific glioma subtypes as potential targets for mutation-specific vaccines. One such example is IDH1R132H, a mutation occurring in 70-80% of diffuse and anaplastic gliomas affecting the catalytic site of the protein
Using our platform we have developed a peptide vaccine targeting mutant IDH1. A multicenter phase I clinical study to test the immunogenicity and tolerability of this vaccine in brain tumor patients has started recruiting in July 2015 within the German Cancer Consortium and the German Neurooncology Working Group. This project was paralleled by the development of a companion diagnostic determining presentation of the target antigen in tumor tissue. First results of the trial are expected for the end of 2017, which will be followed by a multicenter successor trial aiming at testing combinatorial approach with the vaccines and – more importantly – determining the intratumoral immune response in patients. Further ongoing projects deal with (a) the mode of action of the vaccine, (b) the identification of further neoepitopes in brain tumors for specific immunotherapy, and (c) the conceptual combination with other immunotherapeutic interventions such as immune checkpoint blockers in brain tumors.