An effective therapeutic regime for treatment of glioma using oncolytic vaccinia virus expressing IL-21 in combination with immune checkpoint inhibition.
An effective therapeutic regime for treatment of glioma using oncolytic vaccinia virus expressing IL-21 in combination with immune checkpoint inhibition.
复制标题
DOI：
10.1016/j.omto.2022.05.008
复制
发表时间：
2022-09-15
期刊：
影响因子：
--
通讯作者：
Wang, Yaohe
中科院分区：
文献类型：
--
作者：
Sun, Yijie;Zhang, Zhe;Zhang, Chenglin;Zhang, Na;Wang, Pengju;Chu, Yongchao;Dunmall, Louisa S. Chard;Lemoine, Nicholas R.;Wang, Yaohe
胶质母细胞瘤（GBM）是脑内最常见的原发性恶性肿瘤，占所有原发性脑肿瘤的51.4%。GBM具有高度免疫抑制的肿瘤微环境（TME），因此，对免疫策略的反应较差。牛痘病毒（VV）是一种溶瘤病毒，在各种肿瘤类型中显示出巨大的治疗效果。除了对肿瘤细胞的直接裂解作用外，它还具有增强免疫细胞浸润到TME中的能力，从而改善对肿瘤的免疫控制。在这里，我们使用了新一代的VV表达的治疗有效载荷白细胞介素-21治疗小鼠GL 261胶质瘤模型。在瘤内和静脉内递送后，病毒治疗诱导TME的重塑以促进稳健的抗肿瘤免疫应答，这导致在皮下和原位小鼠模型中对肿瘤生长和长期存活的控制。与全身性α-PD 1治疗联合使用可显著改善治疗疗效，后者作为单独治疗无效，但与溶瘤VV协同作用可增强治疗结局。重要的是，这项研究还揭示了病毒治疗后干细胞记忆T细胞群的上调，这些细胞群发挥了强大而持久的抗肿瘤活性。携带白细胞介素-21的溶瘤痘苗病毒在胶质瘤的皮下和原位模型中是一种有效的治疗方法，并与α-PD 1协同促进肿瘤清除。治疗导致诱导有效的适应性免疫应答，包括发挥强而持久的抗肿瘤活性的干细胞记忆T细胞应答。
Glioblastoma (GBM) is the most common primary malignant tumor in the brain, accounting for 51.4% of all primary brain tumors. GBM has a highly immunosuppressive tumor microenvironment (TME) and, as such, responses to immunotherapeutic strategies are poor. Vaccinia virus (VV) is an oncolytic virus that has shown tremendous therapeutic effect in various tumor types. In addition to its directly lytic effect on tumor cells, it has an ability to enhance immune cell infiltration into the TME allowing for improved immune control over the tumor. Here, we used a new generation of VV expressing the therapeutic payload interleukin-21 to treat murine GL261 glioma models. After both intratumoral and intravenous delivery, virus treatment induced remodeling of the TME to promote a robust anti-tumor immune response that resulted in control over tumor growth and long-term survival in both subcutaneous and orthotopic mouse models. Treatment efficacy was significantly improved in combination with systemic α-PD1 therapy, which is ineffective as a standalone treatment but synergizes with oncolytic VV to enhance therapeutic outcomes. Importantly, this study also revealed the upregulation of stem cell memory T cell populations after the virus treatment that exert strong and durable anti-tumor activity. Oncolytic vaccinia virus armed with interleukin-21 is an effective treatment in subcutaneous and orthotopic models of glioma and synergizes with α-PD1 to promote tumor clearance. Treatment results in induction of potent adaptive immune responses, including stem cell memory T cell responses that exert strong and durable anti-tumor activity.
登录
查看更多内容
影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
影响因子：
20.3
作者：
Castermans, Karolien;Tabruyn, Sebastien P.;Griffioen, Arjan W.
通讯作者：
Griffioen, Arjan W.
影响因子：
5.7
作者：
Jounai N;Kobiyama K;Takeshita F;Ishii KJ
通讯作者：
Ishii KJ
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
7.3
作者：
Chen Z;Hambardzumyan D
通讯作者：
Hambardzumyan D