Funded Project 02

Glioblastoma cells produce certain molecules such as the PD-1 ligand to evade attacks from immune cells by inactivating them. The project aims to override this mechanism.

For this purpose, after infection of tumor cells with a virus system derived from human adeno-associated viruses (HER2-AAV), antibody fragments, so-called immunoadhesins, are produced in them, which are intended to block the interaction of PD-L1 with its receptor on immune cells. The local production of immunoadhesin is intended to efficiently unblock the immune reaction directed against the tumor and at the same time avoid systemic side effects. The combination of HER2-AAVs with natural killer (CAR-NK) cells directed against glioblastoma cells is based on complementary mechanisms of action and can therefore potentially achieve synergistic effects. The CAR-NK cells lyse tumor cells, resulting in an increased release of tumor-specific antigens and a local immune reaction directed against the tumor. The intratumoral release of immune adhesins mediated by the HER2-AAVs in turn unblocks and strengthens this immune response very specifically in the tumor.

In the preclinical tests, we are been able to show that the mechanisms of action of both therapeutic approaches actually reinforce each other. In the currently planned laboratory experiments based on this preliminary work, the cellular and molecular mechanisms of the immune response achieved will be characterized in detail. For this purpose, several model systems are used that imitate the human tumor in accurate detail. For example, “tumor organoids” are used to recreate the human glioblastoma, including its most important components, in a test tube. The characterization of the changes achieved should be compared with the corresponding results from the CAR2BRAIN study. This clinical trial is currently evaluating CAR-NK cell therapy in combination with checkpoint inhibition in patients with glioblastoma.

The funding of this project by the Anni Hofmann Foundation makes an important contribution to the further development of immunotherapies for glioblastomas.