Bausart Mathilde, Vanvarenberg Kevin, Ucakar Bernard, Lopes Alessandra, Vandermeulen Gaëlle, Malfanti Alessio, Préat Véronique
Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, UCLouvain, 1200 Brussels, Belgium.
Pharmaceutics. 2022 May 10;14(5):1025. doi: 10.3390/pharmaceutics14051025.
Combination immunotherapy has emerged as a promising strategy to increase the immune response in glioblastoma (GBM) and overcome the complex immunosuppression occurring in its microenvironment. In this study, we hypothesized that combining DNA vaccines-to stimulate a specific immune response-and dual immune checkpoint blockade (ICB)-to decrease the immunosuppression exerted on T cells-will improve the immune response and the survival in an orthotopic unresectable GL261 model. We first highlighted the influence of the insertion position of a GBM epitope sequence in a plasmid DNA vaccine encoding a vesicular stomatitis virus glycoprotein (VSV-G) (here referred to as pTOP) in the generation of a specific and significant IFN-γ response against the GBM antigen TRP2 by inserting a CD8 epitope sequence in specific permissive sites. Then, we combined the pTOP vaccine with anti-PD-1 and anti-CTLA-4 ICBs. Immune cell analysis revealed an increase in effector T cell to Treg ratios in the spleens and an increase in infiltrated IFN-γ-secreting CD8 T cell frequency in the brains following combination therapy. Even if the survival was not significantly different between dual ICB and combination therapy, we offer a new immunotherapeutic perspective by improving the immune landscape in an orthotopic unresectable GBM model.
联合免疫疗法已成为一种有前景的策略，可增强胶质母细胞瘤（GBM）的免疫反应，并克服其微环境中发生的复杂免疫抑制。在本研究中，我们假设将DNA疫苗（用于刺激特异性免疫反应）与双重免疫检查点阻断（ICB）（用于减少对T细胞施加的免疫抑制）相结合，将改善原位不可切除的GL261模型中的免疫反应和生存期。我们首先通过在特定允许位点插入CD8表位序列，突出了胶质母细胞瘤表位序列在编码水疱性口炎病毒糖蛋白（VSV-G）的质粒DNA疫苗（此处称为pTOP）中的插入位置，对针对GBM抗原TRP2产生特异性且显著的IFN-γ反应的影响。然后，我们将pTOP疫苗与抗PD-1和抗CTLA-4 ICB相结合。免疫细胞分析显示，联合治疗后脾脏中效应T细胞与调节性T细胞的比例增加，且大脑中浸润的分泌IFN-γ的CD8 T细胞频率增加。即使双重ICB与联合治疗之间的生存期无显著差异，我们通过改善原位不可切除GBM模型中的免疫格局，提供了一种新的免疫治疗观点。
