A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer.
A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer.
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DOI：
10.1136/jitc-2020-001624
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发表时间：
2021-01
影响因子：
10.9
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Marelli G;Chard Dunmall LS;Yuan M;Di Gioia C;Miao J;Cheng Z;Zhang Z;Liu P;Ahmed J;Gangeswaran R;Lemoine N;Wang Y
胰腺癌仍然是最致命的癌症之一，并且对免疫干预是难治的。溶瘤病毒是一种很有前途的新治疗选择，但目前的平台显示出有限的疗效，特别是对于需要全身可递送疗法的不可及和转移性癌症。我们最近描述了一种溶瘤性痘苗病毒（VV），VVLΔTKΔ N1 L，其具有强效抗肿瘤活性，以及通过药理学抑制PI 3激酶δ（PI 3 K δ）的药理学抑制来增强VV的静脉内递送以防止病毒被巨噬细胞摄取的方案。虽然这些平台改善了VV的临床前景，但必须提高抗肿瘤疗效。对VVLΔTKΔ N1 L进行修饰，以通过病毒B5 R蛋白修饰改善肿瘤内和肿瘤间的病毒传播，这增强了VV的细胞外包膜病毒形式的产生。通过用白细胞介素-21武装病毒，产生VVL-21，提高了病毒治疗引起的抗肿瘤免疫。在胰腺癌小鼠和叙利亚仓鼠模型中全身给药后，评估了其疗效、功能活性和与α-程序性细胞死亡蛋白1（α-PD 1）的协同作用。VVL-21在全身递送后可到达肿瘤，并在胰腺癌的皮下、原位和播散模型中显示出抗肿瘤功效。修饰的B5 R的掺入改善了VV的肿瘤内积累。VVL-21治疗增加了肿瘤内效应CD 8 + T细胞的数量，增加了循环自然杀伤细胞，并能够在体内和体外将巨噬细胞转化为M1表型。重要的是，用VVL-21治疗使肿瘤对免疫检查点抑制剂α-PD 1敏感。腹腔内施用VVL-21成功地重塑了抑制性肿瘤微环境，以促进抗肿瘤免疫应答并改善胰腺癌动物模型的长期存活。重要的是，用VVL-21治疗使肿瘤对免疫检查点抑制剂α-PD 1敏感。PI 3 K δ抑制、VVL-21和α-PD 1的组合创建了治疗胰腺癌的有效平台。
Pancreatic cancer remains one of the most lethal cancers and is refractory to immunotherapeutic interventions. Oncolytic viruses are a promising new treatment option, but current platforms demonstrate limited efficacy, especially for inaccessible and metastatic cancers that require systemically deliverable therapies. We recently described an oncolytic vaccinia virus (VV), VVLΔTKΔN1L, which has potent antitumor activity, and a regime to enhance intravenous delivery of VV by pharmacological inhibition of pharmacological inhibition of PI3 Kinase δ (PI3Kδ) to prevent virus uptake by macrophages. While these platforms improve the clinical prospects of VV, antitumor efficacy must be improved. VVLΔTKΔN1L was modified to improve viral spread within and between tumors via viral B5R protein modification, which enhanced production of the extracellular enveloped virus form of VV. Antitumor immunity evoked by viral treatment was improved by arming the virus with interleukin-21, creating VVL-21. Efficacy, functional activity and synergy with α-programmed cell death protein 1 (α-PD1) were assessed after systemic delivery to murine and Syrian hamster models of pancreatic cancer. VVL-21 could reach tumors after systemic delivery and demonstrated antitumor efficacy in subcutaneous, orthotopic and disseminated models of pancreatic cancer. The incorporation of modified B5R improved intratumoural accumulation of VV. VVL-21 treatment increased the numbers of effector CD8+ T cells within the tumor, increased circulating natural killer cells and was able to polarize macrophages to an M1 phenotype in vivo and in vitro. Importantly, treatment with VVL-21 sensitized tumors to the immune checkpoint inhibitor α-PD1. Intravenously administered VVL-21 successfully remodeled the suppressive tumor-microenvironment to promote antitumor immune responses and improve long-term survival in animal models of pancreatic cancer. Importantly, treatment with VVL-21 sensitized tumors to the immune checkpoint inhibitor α-PD1. Combination of PI3Kδ inhibition, VVL-21 and α-PD1 creates an effective platform for treatment of pancreatic cancer.
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影响因子：
20.3
作者：
Castermans, Karolien;Tabruyn, Sebastien P.;Griffioen, Arjan W.
通讯作者：
Griffioen, Arjan W.
DOI：
10.5414/cp202474
发表时间：
2016-04-01
影响因子：
0.8
作者：
Ignatenko, Stanislav;Skrumsager, Birte K.;Mouritzen, Ulrik
通讯作者：
Mouritzen, Ulrik
影响因子：
11.2
作者：
Ahmad, Shamim;Abu-Eid, Rasha;Khleif, Samir N.
通讯作者：
Khleif, Samir N.
影响因子：
5.1
作者：
通讯作者：
--
影响因子：
4.4
作者：
Li, YQ;Bleakley, M;Yee, C
通讯作者：
Yee, C