溶瘤病毒联合检查点抑制剂疗法或能有效治疗乳腺癌和黑...

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免疫疗法能够帮助机体免疫系统有效抵御癌症，这种疗法为癌症的治疗带来了革命性的突破，比如治疗黑色素瘤和白血病等多种癌症等，但免疫疗法依然无法有效治疗很多种类型的癌症。近日，来自渥太华医院和渥太华大学的研究人员通过对小鼠进行研究发现，将溶瘤病毒同检查点抑制剂疗法结合的一种新型组合性免疫疗法或能有效成功治疗乳腺癌及其它多种类型的癌症，相关成果刊登于国际杂志Science Translational Medicine上。

图片来源：The Ottawa Hospital

研究者Marie-Claude Bourgeois-Daigneault表示，我们很意外地发现利用这种新型组合性疗法能够治愈大部分患癌小鼠，甚至是一些对免疫疗法产生耐药性的小鼠；我们认为，相同的机制在人类癌症中或许也会发生作用，但后期还需要进行更为深入的研究在人类机体中进行证实。

当前研究中，研究人员重点对三阴性乳腺癌进行研究，这是一种恶性且非常难以治疗的乳腺癌。研究者对三只三阴性乳腺癌小鼠模型进行研究发现，这些患癌小鼠对检查点抑制剂疗法均产生了一定的耐药性，同时他们还发现，当一种名为Maraba的溶瘤病毒在这些患癌小鼠机体中复制时，似乎能帮助小鼠的免疫系统有效识别并且攻击癌症，然而单一的溶瘤病毒疗法似乎对小鼠的总体生存率影响甚微。

随后研究者对术后模拟乳腺癌转移扩散的小鼠模型进行研究，检测了溶瘤病毒结合检查点抑制剂疗法对模型的作用效果，结果发现，这种组合性疗法能治疗60%至90%的患癌小鼠，而单独使用检查点抑制剂的治愈率为0%，单独使用溶瘤病毒疗法的治愈率也仅有20%至30%，对于这些患癌模型而言，研究人员在术前给予模型病毒治疗，同时在术后进行检查点抑制剂疗法治疗。

研究者Bell说道，我们的免疫系统会持续识别并且杀灭癌细胞，但癌细胞也总是会尝试躲避机体免疫系统的识别作用，当将病毒注射到癌细胞中时，似乎就生气了一面巨大的国旗，其能帮助免疫系统来识别并且攻击癌细胞；但在某些类型的癌症中似乎这种方法作用有限，研究者指出，当癌细胞感染病毒后加入检查点抑制剂疗法，其就会释放所有警报，提醒免疫系统有效攻击癌症。

近来研究人员进行的一项临床试验也证实，溶瘤病毒和检查点抑制剂疗法联合后能有效治疗黑色素瘤，但本文研究中研究人员首次证实这种组合性疗法可以成功治疗乳腺癌；当然这项研究中研究者也首次尝试在手术和癌症转移模型中检测病毒和检查点抑制剂疗法的联合作用效果，对于临床中患者的治疗而言具有重要价值。

（生物谷Bioon.com）

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Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade

Adel Samson1,*, Karen J. Scott1,†, David Taggart1,†, Emma J. West1, Erica Wilson1, Gerard J. Nuovo2, Simon Thomson3, Robert Corns3, Ryan K. Mathew1, Martin J. Fuller1, Timothy J. Kottke4, Jill M. Thompson4, Elizabeth J. Ilett1, Julia V. Cockle1, Philip van Hille3, Gnanamurthy Sivakumar3, Euan S. Polson1, Samantha J. Turnbull1, Elizabeth S. Appleton1, Gemma Migneco1, Ailsa S. Rose1, Matthew C. Coffey5, Deborah A. Beirne3, Fiona J. Collinson6, Christy Ralph1, D. Alan Anthoney1, Christopher J. Twelves1, Andrew J. Furness7, Sergio A. Quezada7, Heiko Wurdak1, Fiona Errington-Mais1, Hardev Pandha8, Kevin J. Harrington9, Peter J. Selby1, Richard G. Vile4, Stephen D. Griffin1, Lucy F. Stead1, Susan C. Short1,*,‡ and Alan A. Melcher

Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

http://stm.sciencemag.org/content/10/422/eaam7577

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Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy

Marie-Claude Bourgeois-Daigneault1,2,*, Dominic Guy Roy1,2,†, Amelia Sadie Aitken1,2,†, Nader El Sayes1,2,†, Nikolas Tim Martin1,2, Oliver Varette1,2, Theresa Falls1, Lauren Elizabeth St-Germain1, Adrian Pelin1,2, Brian Dennis Lichty3, David Francis Stojdl2,4, Guy Ungerechts1, Jean-Simon Diallo1,2 and John Cameron Bell

Triple-negative breast cancer (TNBC) is an aggressive disease for which treatment options are limited and associated with severe toxicities. Immunotherapeutic approaches like immune checkpoint inhibitors (ICIs) are a potential strategy, but clinical trials have demonstrated limited success in this patient cohort. Clinical studies using ICIs have revealed that patients with preexisting anticancer immunity are the most responsive. Given that oncolytic viruses (OVs) induce antitumor immunity, we investigated their use as an ICI-sensitizing approach. Using a therapeutic model that mimics the course of treatment for women with newly diagnosed TNBC, we demonstrate that early OV treatment coupled with surgical resection provides long-term benefits. OV therapy sensitizes otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals. We suggest that OV therapy in combination with immune checkpoint blockade warrants testing as a neoadjuvant treatment option in the window of opportunity between TNBC diagnosis and surgical resection.

http://stm.sciencemag.org/content/10/422/eaao1641