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.

中文翻译：

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DNA 疫苗和免疫检查点阻断剂的结合提高了原位不可切除胶质母细胞瘤模型中的免疫反应

联合免疫疗法已成为提高胶质母细胞瘤 (GBM) 免疫反应并克服其微环境中发生的复杂免疫抑制的一种有前途的策略。在这项研究中，我们假设结合 DNA 疫苗（刺激特定的免疫反应）和双重免疫检查点阻断 (ICB)（减少对 T 细胞施加的免疫抑制）将改善原位不可切除 GL261 模型的免疫反应和存活率. 我们首先强调了 GBM 表位序列在编码水疱性口炎病毒糖蛋白 (VSV-G)（此处称为 pTOP）的质粒 DNA 疫苗中的插入位置在产生针对针对通过在特定的允许位点插入 CD8 表位序列来检测 GBM 抗原 TRP2。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 Treg 的比率增加，脑中浸润的 IFN-γ 分泌 CD8 T 细胞频率增加。即使双重 ICB 和联合治疗之间的存活率没有显着差异，我们通过改善原位不可切除 GBM 模型中的免疫景观来提供新的免疫治疗观点。