Exploiting 4-1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine gliomas.
Exploiting 4-1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine gliomas.
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利用4-1BB免疫检查点，以增强溶瘤病毒疗法的疗效，对弥漫性内在的蓬托神经胶质瘤。
DOI：
10.1172/jci.insight.154812
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发表时间：
2022-04-08
期刊：
影响因子：
8
通讯作者：
Alonso, Marta M.
中科院分区：
文献类型：
--
作者：
Laspidea, Virginia;Puigdelloses, Montserrat;Labiano, Sara;Marrodan, Lucia;Garcia-Moure, Marc;Zalacain, Marta;Gonzalez-Huarriz, Marisol;Martinez-Velez, Naiara;Ausejo-Mauleon, Iker;de la Nava, Daniel;Herrador-Canete, Guillermo;Marco-Sanz, Javier;Guruceaga, Elisabeth;de Andrea, Carlos E.;Villalba, Maria;Becher, Oren;Squatrito, Massimo;Matia, Veronica;Gallego Perez-Larraya, Jaime;Patino-Garcia, Ana;Gupta, Sumit;Gomez-Manzano, Candelaria;Fueyo, Juan;Alonso, Marta M.
弥漫性桥脑神经胶质瘤（DIPG）是侵袭性儿科脑肿瘤，尽管进行了许多治疗努力，但患者生存率并未改变，强调迫切需要有效的治疗。在这里，我们评估了溶瘤腺病毒Delta-24-ACT的抗DIPG作用，该溶瘤腺病毒被工程化以表达共刺激配体4-1BBL以增强病毒的抗肿瘤免疫应答。Delta-24-ACT诱导感染的DIPG细胞膜上功能性4-1BBL的表达，这增强了CD 8 + T淋巴细胞的共刺激。在体内，鼠DIPG原位肿瘤的Delta-24-ACT治疗显著改善了治疗小鼠的存活率，导致长期存活者对这些肿瘤产生免疫记忆。此外，Delta-24-ACT是安全的，不会引起局部或全身毒性。机制研究表明，Delta-24-ACT调节肿瘤免疫含量，不仅增加了免疫细胞的数量，而且改善了免疫细胞的功能。所有这些数据都突出了Delta-24-ACT治疗DIPG患者的安全性和潜在治疗获益。
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors, and patient survival has not changed despite many therapeutic efforts, emphasizing the urgent need for effective treatments. Here, we evaluated the anti-DIPG effect of the oncolytic adenovirus Delta-24-ACT, which was engineered to express the costimulatory ligand 4-1BBL to potentiate the antitumor immune response of the virus. Delta-24-ACT induced the expression of functional 4-1BBL on the membranes of infected DIPG cells, which enhanced the costimulation of CD8+ T lymphocytes. In vivo, Delta-24-ACT treatment of murine DIPG orthotopic tumors significantly improved the survival of treated mice, leading to long-term survivors that developed immunological memory against these tumors. In addition, Delta-24-ACT was safe and caused no local or systemic toxicity. Mechanistic studies showed that Delta-24-ACT modulated the tumor-immune content, not only increasing the number, but also improving the functionality of immune cells. All of these data highlight the safety and potential therapeutic benefit of Delta-24-ACT the treatment of patients with DIPG.
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影响因子：
9
作者：
Fucikova J;Kepp O;Kasikova L;Petroni G;Yamazaki T;Liu P;Zhao L;Spisek R;Kroemer G;Galluzzi L
通讯作者：
Galluzzi L
DOI：
10.1158/1541-7786.mcr-16-0389
发表时间：
2017-09
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Cordero FJ;Huang Z;Grenier C;He X;Hu G;McLendon RE;Murphy SK;Hashizume R;Becher OJ
通讯作者：
Becher OJ
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
45.3
作者：
Lang, Frederick F.;Conrad, Charles;Fueyo, Juan
通讯作者：
Fueyo, Juan
影响因子：
3.7
作者：
Barton KL;Misuraca K;Cordero F;Dobrikova E;Min HD;Gromeier M;Kirsch DG;Becher OJ
通讯作者：
Becher OJ