Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma
Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma
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DOI：
10.1093/neuonc/nox139
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发表时间：
2018-02-01
期刊：
影响因子：
15.9
通讯作者：
Lawler, Sean E.
中科院分区：
文献类型：
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作者：
Speranza, Maria-Carmela;Passaro, Carmela;Lawler, Sean E.
联合免疫疗法是一种很有前途的癌症治疗方法。为探讨抗程序性细胞死亡蛋白1(PD-1)联合基因介导的细胞毒免疫治疗(GMCI)对胶质母细胞瘤中PD配体1(PD-L1)表达的影响，我们通过瘤内注射非复制型腺病毒(ADV-tk)进行原位化疗和免疫刺激。在两种同基因小鼠胶质母细胞瘤模型(GL261和CT-2A)上观察联合应用的疗效。用流式细胞仪分析免疫渗入细胞，GMCI在体外和体内均上调PD-L1的表达。GMCI和抗PD-1抗体均可增加T细胞在瘤内的浸润。与单一治疗相比，GMCI/抗PD-1联合治疗的小鼠的长期存活率更高。长期存活的患者免受肿瘤再攻击，表现出持久的记忆抗肿瘤免疫力。GMCI导致干扰素-γ阳性T细胞升高，耗竭的PD1+TIM+CD8+双阳性T细胞比例降低。GMCI还增加了肿瘤细胞和浸润性巨噬细胞/小胶质细胞上PD-L1的水平。我们的数据表明，抗PD-1治疗通过克服干扰素诱导的PD-L1介导的抑制信号来提高GMCI的有效性，而GMCI通过增加肿瘤浸润性T细胞的激活来提高抗PD-1的有效性。我们的数据表明，GMCI/抗PD-1联合治疗在胶质母细胞瘤小鼠模型中具有良好的耐受性和有效性。这些结果支持在胶质母细胞瘤患者中对这种联合治疗的评估。
Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation.The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry.GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti-PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti-PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti-PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1-mediated inhibitory signals, and GMCI improves anti-PD-1 efficacy by increasing tumor-infiltrating T-cell activation.Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.