Glioblastoma (GB) is the most common primary brain tumor which is characterized by a low immunogenicity of tumor cells and a prevalent immunosuppression in the tumor microenvironment (TME). Since expression of PD-L1 on GB cells has been described, immunotherapy with checkpoint inhibitors (CIs) may be a promising approach for GB treatment. However, systemic administration of CIs bears the risk of autoimmune-like side effects. Delivery of CIs through targeted Adeno-associated viral vectors (AAVs) could overcome this problem. While the brain is HER2(ErbB2)-negative, GB are frequently HER2-positive. Accordingly, intratumoral administration of HER2-specific AAVs encoding CIs may represent a promising approach for GB immunotherapy. This approach will be further combined with local injection of HER2-specific CAR-NK cells (NK-92/5.28.z). The CAR-NK cells already demonstrated efficacy in preclinical GB models and are currently under investigation in the CAR2BRAIN phase I clinical trial. AAVs used in this project harbor a HER2-specific DARPin and encode a murine PD-1 inhibitor (aPD-1). Subcutaneous GL261-HER2 tumors were treated locally with HER2-AAVs either alone or in combination with HER2-specific NK-92/5.28.z cells, and tumor growth and survival were monitored. Subsequently, the efficacy of local application will be compared to systemic AAV administration in subcutaneous and orthotopic intracranial tumors. AAV distribution and specific tumor cell targeting will also be analyzed. Furthermore, future experiments will investigate the influence of AAVs on the TME and the immune cell composition of tumors. Transduction efficacy of HER2-AAVs in murine as well as human glioma cells in vitro correlates with the level of HER2 expression. Subsequently, aPD-1 is secreted in a time-dependant manner and binds its target on PD-1-expressing cells. Preliminary results suggest combined therapy with aPD-1-encoding HER2-AAVs and NK-92/5.28.z cells to mediate anti-tumor effects in vivo. Comparison of local and systemic administration of HER2-AAVs in subcutaneous and intracranial GL26-HER2 tumors is still subject of ongoing investigation, as well as analysis of tumor cell penetration by AAVs in vivo. Local therapy with HER2-AAV in combination with HER2-CAR NK cells is a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce side effects, potentially offering perspectives beyond brain tumor medicine.
Disclosure Information M.I. Strecker: None. F. Strassheimer: None. J. Reul: None. P.N. Harter: None. T. Tonn: None. J.P. Steinbach: None. W.S. Wels: None. C.J. Buchholz: None. M.C. Burger: None.
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