A novel vesicular stomatitis virus armed with IL-2 mimic for oncolytic therapy

Manman Wu; Yiwei Wang; Chuanjian Wu; Huang Huang; Xinyuan Zhou; Jun Wang; Sidong Xiong; Chunsheng Dong

doi:10.1016/j.virs.2024.09.007

October 2024

. doi: 10.1016/j.virs.2024.09.007

Citation: Manman Wu, Yiwei Wang, Chuanjian Wu, Huang Huang, Xinyuan Zhou, Jun Wang, Sidong Xiong, Chunsheng Dong. A novel vesicular stomatitis virus armed with IL-2 mimic for oncolytic therapy .VIROLOGICA SINICA, 2024, 39(5) : 821-832. http://dx.doi.org/10.1016/j.virs.2024.09.007

一种携有IL-2类似物的新型水疱性口炎病毒用于溶瘤治疗

吴曼曼 ^a ,
王奕炜 ^a ,
武传建 ^a ,
黄煌 ^b ,
周新元 ^c,, ,
王俊 ^a,, ,
熊思东 ^a,, ,
董春升 ^a,,

cstr: 32224.14.j.virs.2024.09.007

a. 苏州大学生物与医学研究所, 老年病与免疫学教育部重点实验室, 江苏省感染与免疫重点实验室;
b. 河北承德市981医院;
c. 陆军军医大学基础医学院免疫学研究所

通讯作者： 周新元, xinyuanzhou@tmmu.edu.cn; 王俊, jwang79@suda.edu.cn; 熊思东, sdxiong@suda.edu.cn; 董春升, chunshengdong@suda.edu.cn
收稿日期： 2024-02-16
录用日期： 2024-09-11

摘要

作为癌症免疫疗法的一种新载体，溶瘤病毒（Oncolytic virus, OV）正迅速为人们所知晓。越来越多的证据表明，OV能够改变肿瘤微环境的免疫状态，即将所谓的“冷”肿瘤转化为“热”肿瘤。OV可以改善机体抗肿瘤免疫，并通过联合各种免疫调节剂进一步增强抗肿瘤免疫应答。Neo-2/15是一种新合成的细胞因子，同时具有IL-2和IL-15的功能。然而，它缺乏结合IL-2受体α亚基（CD25）的位点，因此无法诱导Treg增殖。在本研究中，我们构建了一种表达Neo-2/15的重组水疱性口炎病毒（VSVM51R-Neo-2/15）。VSVM51R-Neo-2/15的瘤内递送有效地抑制了小鼠肿瘤的生长，没有引发临床上与IL-2相关的毒性反应。此外，VSVM51R-Neo-2/15的治疗增加了肿瘤中活化的 CD8+ T细胞的数量，但没有增加Treg细胞的数量。VSVM51R-Neo-2/15治疗后有更多的荷瘤小鼠存活下来，且存活的小鼠在再次挑战肿瘤细胞时表现出增强的抗肿瘤免疫保护。此外，OV和抗PD-L1免疫检查点抑制剂的联合治疗进一步增强了小鼠的抗肿瘤免疫反应。这些研究结果初步表明，VSVM51R-Neo-2/15可有效抑制肿瘤生长，提高对免疫检查点抑制剂的敏感性，为进一步的临床试验提供了有希望的初步尝试。
- 联合治疗
- , IL-2类似物
- , Neo-2/15
- , 溶瘤病毒
- , 肿瘤免疫
- , 水疱性口炎病毒

A novel vesicular stomatitis virus armed with IL-2 mimic for oncolytic therapy

Manman Wu ^a ,
Yiwei Wang ^a ,
Chuanjian Wu ^a ,
Huang Huang ^b ,
Xinyuan Zhou ^c,, ,
Jun Wang ^a,, ,
Sidong Xiong ^a,, ,
Chunsheng Dong ^a,,

a. The Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215123, China;
b. Department of Cardiology, No. 981 Hospital, PLA (People's Liberation Army of China), Chengde 067000, China;
c. Institute of Immunology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China

Corresponding author: Xinyuan Zhou, xinyuanzhou@tmmu.edu.cn Jun Wang, jwang79@suda.edu.cn Sidong Xiong, sdxiong@suda.edu.cn Chunsheng Dong, chunshengdong@suda.edu.cn
Received Date: 16 February 2024
Accepted Date: 11 September 2024

Abstract

Oncolytic virus (OV) is increasingly being recognized as a novel vector in cancer immunotherapy. Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment, so called transformation of ‘cold’ tumors into ‘hot’ tumors. The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators. The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15. However, it specifically lacks the binding site of IL-2 receptor α subunit (CD25), therefore unable to induce the Treg proliferation. In present study, a recombinant vesicular stomatitis virus expressing the Neo-2/15 (VSV^M51R-Neo-2/15) was generated. Intratumoral delivery of VSV^M51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic. Moreover, treatment with VSV^M51R-Neo-2/15 increased the number of activated CD8⁺ T cells but not Treg cells in tumors. More tumor-bearing mice were survival with VSV^M51R-Neo-2/15 treatment, and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity. In addition, combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response. These findings suggest that our novel VSV^M51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors, providing promising attempts for further clinical trials.
- Combination therapy
- , IL-2 mimic
- , Neo-2/15
- , Oncolytic virus (OV)
- , Tumor immunity
- , Vesicular Stomatitis virus (VSV)

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