Presentation of currently funded projects

 

01.01.2020 – 31.12.2021
In the current funding period, three projects are currently being supported based on the results of previous periods. Further possible funding projects are currently under evaluation.

Targeted local combination therapy with checkpoint inhibitors and CAR-NK cells in glioblastoma using DARPin-linked AAV vectors

Head of the project: Dr. Michael Burger, Clinic Johann Wolfgang Goethe-University Frankfurt/Main

 

The intratumoral blockade of the immune system is characteristic for glioblastoma and can be counteracted with immune checkpoint inhibitors (ICI). However, side effects and complications often occur after intravenous administration of ICI. The combination of multiple ICI results in an amplification of potential side effects, which means that such combination therapies are only feasible to a very limited extent. Local intratumoral production of ICI in glioblastoma can be achieved by the administration of "adeno-associated viruses" (AAVs). The AAVs used in this project are replication-incompetent viral vectors which harbor the coding sequence for ICI and are specifically targeted against the HER2 protein by a “designed ankyrin repeat protein” (DARPin), so that only HER2-positive cells can be transduced. HER2 is often present on the surface of glioblastoma cells, but not on the surface of other brain cells. The local production of ICI results in a high intratumoral concentration, counteracting the immunosuppressive microenvironment. Only a small proportion of the ICI produced in the tumor reaches the blood, potentially minimizing the risk for side effects. The combination of local ICI therapy with local cellular immunotherapy with CAR-NK cells is particularly promising. CAR-NK cells are natural killer cells, which by means of a “chimeric antigen receptor” (CAR) are directed against the HER2 protein. CAR-NK cells can thus specifically identify and destroy glioblastoma cells, thereby triggering an anti-tumor immune response. The local ICI production results in a reduction of the immunosuppressive microenvironment, and an increase of the immune response. The aim of this project is to characterize the possibly synergistic effects of the local ICI therapy in addition to the local cellular immunotherapy with CAR-NK cells. As a perspective, we aim to investigate whether local combination therapies with  multiple HER2-AAVs can be harnessed to resolve the blockade of the immune system in the tumor.

Scheme depicting the intended synergistic effect between CAR-NK cells and HER2-AAVs. CAR-NK cells induce an immune reaction directed against the tumor cells, which however is inhibited by the immunosuppressive microenvironment (A). HER2-AAVs transduce HER2+ tumor cells and thereby induce the local production of an immune checkpoint inhibitor (B). The combination of local CAR-NK cell therapy and local immune checkpoint blockade might modify the immunosuppressive microenvironment and induce an immune response even in advanced tumors.

Immunomodulatory effects of anti-angiogenic treatment and radiotherapy in glioblastoma models

Head of the project: Prof. Dr. Katrin Lamszus, University Hospital for Neurosurgery Hamburg

 

The current era of glioblastoma treatment is being redefined by immunotherapeutic approaches. Immune checkpoint inhibitors, viral therapies and vaccination strategies are the most prominent modalities and progressively enter the clinical practice. However, the effects of immunotherapy have not yet reached their full potential and the biology of cancer immune escape, which hinders the execution of efficient immune-mediated cancer elimination, is not yet fully understood. An important problem in immunotherapy of glioblastomas is that the vast majority of patients require corticosteroids to treat tumor-associated brain edema and that steroids have potent immunosuppressive effects. Avastin is an antibody directed against vascular endothelial growth factor (VEGF) that has anti-angiogenic as well as anti-edematous effects and can be combined with immunotherapy. Interestingly, VEGF further has immunosuppressive effects, so that its antagonization in glioblastoma patients may bring dual benefit. A major goal of our project is therefore to investigate whether the blockade of VEGF creates a more immunostimulatory tumor microenvironment and can help to harness the efficacy of the immune system to eradicate the tumor cells. In addition, the standard treatment regimen of glioblastomas usually involves radiotherapy. Radiation causes an immunogenic type of cell death, which can potentially be exploited to support immunotherapy. Hence, another goal is to characterize the effects of radiotherapy on immune cells in the tumor and periphery as well as to determine how clonal heterogeneity is affected by radiation and immunotherapy. The proposed project will provide novel insight into the immunomodulatory impact of anti-angiogenic therapy and radiotherapy, which is highly important to consider when glioblastoma patients are treated with multiple of these modalities. Abbreviations: VEGF, vascular endothelial growth factor, FACS, fluorescence activated cell sorting; TCRseq, T cell receptor sequencing; RGB, red-green-blue lentiviral marking; OBC, optical barcoding.

Local progenitors shape neo-angiogenesis in glioblastoma

Head of the project: Prof. Dr. Rainer Glaß, University Hospital for Neurosurgery Munich

 

Glioblastoma (GBM) depend on support by their local environment. Vascular cells as well as tumour-associated myeloid cells (TAM) constitute the major components of the GBM-parenchyma. We identified a previously unacknowledged population of tumor-associated cells with a myeloid expression profile (TAMEP), which are not of bone-marrow origin and not microglia-derived. TAMEP transiently appear in an early stage of glioblastoma growth and promote pathological angiogenesis in GBM. Using transgenic in vivo models for lineage-tracing of tumor-parenchymal cells, we observed (by single cell transcriptomics and immunofluorescence analysis) TAMEP over a time-course. In different transgenic and bone-marrow chimeric models we investigated the point-of-origin as well as the lineage-identity of these cells. TAMEP were further characterized by immunofluorescence in preclinical models ex vivo and patient samples of GBM. Strikingly, we found that TAMEP are generated by a local, Sox2-dependent progenitor cell. Abrogation of this progenitor cell-population by conditional Sox2-knockout ablated the entire subset of TAMEP. Histopathological inspection showed that the small subset of TAMEP has large impact on disease-progression by controlling glioblastoma-vascularization and -size. Altogether, our data indicate that dormant progenitors generate TAMEP (which are cells expressing myeloid markers but lacking a myeloid origin) that have profound neurooncological impact and point towards a new and promising therapeutic target in order to support anti-angiogenic regimen in GBM.

 

 

 

„The Anni Hofmann Foundation enables researchers to explore new treatment strategies for glioblastoma by providing promising perspectives for emerging concepts. The studies are regularly critically analyzed, openly discussed and continuously developed.“ 

 

Prof. Dr. Rainer Glass