Oncolytic Newcastle disease virus expressing a checkpoint inhibitor as a radioenhancing agent for murine melanoma
Oncolytic Newcastle disease virus expressing a checkpoint inhibitor as a radioenhancing agent for murine melanoma
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DOI：
10.1016/j.ebiom.2019.10.032
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发表时间：
2019-11-01
期刊：
影响因子：
11.1
通讯作者：
Goff, Peter H.
中科院分区：
文献类型：
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作者：
Vijayakumar, Gayathri;Palese, Peter;Goff, Peter H.
背景：针对抗肿瘤T细胞的负调节分子或检查点分子(如PD1/PD-L1和CTLA4)的单抗在治疗多种肿瘤疾病方面已显示出临床疗效。虽然许多患者对检查点抑制剂有显著的反应，但大多数患者表现出不良反应。了解检查点抑制剂如何加强现有的化疗或放射治疗方案或其他免疫疗法，如溶瘤病毒，可能会带来更好的临床结果，以提高疗效和降低毒性来衡量。在这里，我们评估了新城疫病毒(NDV)，一种临床测试中的溶瘤病毒，如何与放射治疗相互作用，以增强检查点抑制物的阻断。方法：利用免疫活性B16-F10小鼠黑色素瘤模型，通常被认为是免疫原性较差或“冷”的肿瘤，询问局部放射治疗与新城疫病毒联合治疗在用抗PD1或抗CTLA4单抗治疗的小鼠中是否比单独治疗更有效。我们还研究了通过瘤内注射表达抗CTLA4单链可变片段(ScFv)的新城疫病毒来局部给予检查点抑制物是否与全身注射抗CTLA4联合放射治疗在介导其抗肿瘤疗效方面具有可比性。应答率的特征是测量随着时间的推移肿瘤大小，观察肿瘤完全消退，以及总存活率。结果：我们的结果显示，在黑色素瘤小鼠模型中，NDV加放射治疗与检查点抑制剂(PD1或CTLA4靶向单抗)相结合，比单独治疗与检查点抑制剂联合治疗的小鼠黑色素瘤模型的肿瘤完全消退率和异常效应要好得多。最后，我们还表明，局部注射表达抗CTLA4加放射的重组新城疫病毒在介导其抗肿瘤效应方面与全身抗CTLA4加放射相当，通过生存效益进行评估。解释：我们的结果表明，溶瘤新城疫病毒加放射治疗与检查点抑制剂一起作用于提高小鼠黑色素瘤的肿瘤清除。新城疫病毒是一种有效的放射治疗剂量节约和免疫治疗剂，能够转基因、体内表达抗CTLA4靶向单链抗体，有可能避免全身暴露。资助：美国国立卫生研究院拨款HHSN272201400 008C。资助者在研究设计、数据收集和分析、决定发表或准备手稿方面没有任何作用。(C)2019年提交人。爱思唯尔出版公司(Elsevier B.V.)
Background: Monoclonal antibodies (mAbs) targeting negative regulators, or checkpoint molecules (e.g. PD1/PD-L1 & CTLA4), of anti-tumoural T cells have demonstrated clinical efficacy in treating several neoplastic diseases. While many patients enjoy remarkable responses to checkpoint inhibitors, a majority show adverse effects. Understanding how checkpoint inhibitors may augment established chemotherapy or radiotherapy regimens or other immunotherapies like oncolytic viruses may lead to better clinical outcomes measured by improved efficacy with reduced toxicity. Here, we assess how Newcastle disease virus (NDV), an oncolytic virus in clinical testing, may interact with radiotherapy to enhance checkpoint inhibitor blockade.Methods: An immunocompetent B16-F10 murine melanoma model, generally considered to be a poorly immunogenic or "cold" tumour, was utilised to query whether combining localised radiotherapy with NDV may be more effective than either therapy alone in controlling tumours in mice treated with anti-PD1 or anti-CTLA4 monoclonal antibodies. We also investigated whether localised administration of a checkpoint inhibitor through an intratumoural injection of NDV that expresses anti-CTLA4 single-chain variable fragment (scFv) is comparable to systemic administration of anti-CTLA4 when combined with radiation in mediating its anti-tumour efficacy. Response rates were characterised by measuring tumour size over time, observation of complete tumour regression, and overall survival.Findings: Our results show that combining NDV plus radiotherapy with checkpoint inhibitors (PD1 or CTLA4 targeted mAbs) results in significantly better complete tumour regression rates with an abscopal effect in a murine model of melanoma than either single therapy combined with checkpoint inhibitors. Finally, we also show that localised administration of a recombinant NDV expressing anti-CTLA4 plus radiation is comparable to systemic anti-CTLA4 plus radiation in mediating its anti-tumour effect as assayed by survival benefit.Interpretation: Our results show that oncolytic NDV plus radiotherapy work together with checkpoint inhibitors to enhance tumour clearance of murine melanoma. NDV is an effective radiotherapy dose-sparing and immunotherapeutic agent capable of transgenic, in vivo expression of an anti-CTLA4 targeted scFv antibody with the potential to spare systemic exposure.Funding: The National Institutes of Health grant HHSN272201400 008C supported the work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. (c) 2019 The Authors. Published by Elsevier B.V.