OS06.2A Local immunotherapy of glioblastoma via AAV-mediated gene transfer of checkpoint inhibitors in combination with CAR-NK cells. (9th September 2021)

• Record Type: Journal Article
• Authors: Strecker, M I; Wlotzka, K; Strassheimer, F; Reul, J; Harter, P N; Tonn, T; Steinbach, J P; Wels, W S; Buchholz, C J; Burger, M C
• Is Part Of: Neuro-oncology. Volume 23: Supplement 2 (2021)
• Page Start: ii8
• Page End: ii9
• Publication Date: 2021-09-09
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab180.026
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Glioblastoma (GB) is the most common primary brain tumor which is characterized by low immunogenicity of tumor cells and 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, while the intratumoral drug concentration reached may not be sufficient. METHODS: We studied delivery of CIs through targeted Adeno-associated viral vectors (AAVs) encoding an anti PD-1 immunoadhesin (aPD-1) as a novel approach towards local immunotherapy in the syngeneic GL261-HER2 glioma model. Tumor cell-specific delivery was achieved by targeting HER2 via a specific designed ankyrin repeat protein (DARPin). We investigated the effects of this strategy alone and in combination with local injection of HER2-specific CAR-NK cells (NK-92/5.28.z), which have already shown efficacy in preclinical GB models and are currently under investigation in the CAR2BRAIN phase I clinical trial. Furthermore, aPD-1 functionality and cellular response to viral transduction as well as compatibility of both therapy approaches has been evaluated in various in vitro models. RESULTS: HER2-AAV transduction efficacy of GB cells correlated with HER2 expression level, while target cells did not show anti-viral responses upon transduction. After transduction with aPD-1 HER2-AAVs, aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T-cells due to PD-1 blockade. AAV-transduction did not interfere with CAR-NK cell mediated tumor cell lysis. Biodistribution studies in mice revealed the presence of aPD-1 up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 tumors, local treatment with HER2-AAV aPD-1 or HER2-AAV IgG-Fc + NK-92/5.28.z therapy had no significant effect, whereas combination therapy profoundly delayed tumor growth. CONCLUSIONS: Local therapy with aPD-1 encoding HER2-AAVs in combination with NK-92/5.28.z cells is a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce side effects.