Insights into mechanisms of T cell response and resistance in post-treatment multicellular AMPLIFY NEOVAC glioma organoids

The adaptive immune system is able to function as a body’s own defense against malignant cells, hence to fight tumor cells. Here, so-called T cells play a crucial role. In cancer, however, T cells become exhausted and may even act inhibitory on the immune response. Clinical therapies apply so-called immune checkpoint inhibitors (IC), thereby reactivating previously exhausted T cells and hence leading to more effective anti-tumor immune responses.

The majority of diffuse gliomas, particularly malignant brain tumors, which are incurable despite resection, irradiation and chemotherapy, is defined by the so-called IDH1R132H mutation. DKTK scientists have successfully tested an IDH1R132H-based vaccine, which was self-developed, for safety and immunogenicity (i.e. induction of an immune response) in a first-in-human multicenter phase 1 clinical trial that was supported by the DKTK in patients with IDH1R132H-mutated glioma. In the currently recruiting follow-up phase 1 trail AMPLIFY-NEOVAC (NOA21, NCT03893903), this vaccine is combined with an ICI to achieve a sufficient activation of IDH1R132H-specific T cells in the tumor. Tumor tissue that is resected after immunotherapy (IDH1R132H vaccine and Avelumab ICI) start will be analyzed for cellular immune activity of T cells.

Within the AMI2GO consortium, consisting of scientists at DKTK sites in Berlin, Frankfurt, and Heidelberg under the direction of Prof. Michael Platten, Heidelberg, so-called glioma organoids derived from tumor tissue post treatment will be generated and analyzed. Glioma organoids are cultures which, over several weeks, preserve not only the various cell types present in the tumor, such as tumor cells but also stromal and immune cells, but also their three dimensional composition. Thereby, they reflect the patient tumor. In the frame of this project, several potential mechanisms of intratumoral T cell activity under IDH1R132H vaccination and Avelumab ICI will be analyzed in glioma organoids.