Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2023-05-22 eCollection Date: 2023-06-15 DOI:10.1016/j.omto.2023.05.006
Mason J Webb, Timothy Kottke, Benjamin L Kendall, Jack Swanson, Chisom Uzendu, Jason Tonne, Jill Thompson, Muriel Metko, Madelyn Moore, Mitesh Borad, Lewis Roberts, Rosa M Diaz, Michael Olin, Antonella Borgatti, Richard Vile
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Abstract

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-β oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.

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使用顺序原发性和肿瘤逃逸选择性溶瘤病毒的陷阱和伏击疗法。
在多种溶瘤病毒治疗模型中,常见的是早期出现抗肿瘤反应后复发。我们之前已经表明,溶瘤VSV-IFN-β的一线治疗诱导APOBEC蛋白,促进肿瘤逃逸的特异性突变的选择。在B16黑色素瘤逃逸(ESC)细胞中的这些突变中,含有冷休克结构域E1(CSDE1)基因的C-T点突变以最高频率存在,其可用于通过接种病毒内表达的突变CSDE1来伏击ESC细胞。在这里,我们表明携带促进逃逸的CSDE1C-T突变的病毒ESC肿瘤细胞的进化也可以通过病毒学伏击来利用。通过在体内连续递送两种溶瘤VSV,可以治愈原本可以逃避VSV-IFN-β溶瘤病毒治疗的肿瘤。这也促进了抗肿瘤T细胞反应的启动,这可以通过使用CD200激活受体配体(CD200AR-L)肽的免疫检查点阻断来进一步利用。我们的研究结果具有重要意义,因为它们提供了开发溶瘤病毒作为高度特异性、逃避靶向的病毒免疫治疗剂的可能性,可用于多种不同类型的一线癌症治疗后的肿瘤复发。
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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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