溶瘤病毒免疫疗法再获突破!两项成果登Science子刊封面
2018/01/10
在最新一期Science Translational Medicine杂志上,关于溶瘤病毒治疗癌症的新成果登上封面!科学家们用2篇论文证实,溶瘤病毒这类免疫疗法能够通过联合检查点抑制剂对抗多种癌症!在其中一项研究中,治愈率甚至达到了60%-90%!


Bourgeois-Daigneault, Samson and their colleagues show how oncolytic virus treatment improves the efficacy of subsequent immune checkpoint blockade against different cancer types.(图片来源:Science Translational Medicine)

论文一:对抗脑肿瘤

在题为“Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade”的论文中,来自英、美的研究小组发现,一种可直接注射到血液中的病毒——呼肠孤病毒(reovirus)——能够用于治疗患有侵袭性脑肿瘤的患者。


图片来源:Science Translational Medicine

此前,科学家们一直认为,由于血脑屏障的存在,病毒能够从血液进入大脑是不太可能的。这就意味着,研究人员使病毒进入大脑的唯一途径是,直接将病毒注入大脑中。这是非常具有挑战性的,也不能经常重复。然而,在这项新研究中,单次剂量的静脉滴注就实现了让病毒进入大脑中。

具体来说,研究包含的9名患者要么是身体其他部位的癌症扩散到了大脑中,要么患上了快速生长的神经胶质瘤一种难治的、预后较差的脑癌)。所有的病人都要手术切除肿瘤。但在进行手术的前几天,病人被注射了病毒。

在肿瘤被切除后,研究人员采集了样本,用以分析病毒是否抵达了大脑肿瘤部位。结果显示,在所有患者中,这些病毒都“成功了”。另外,呼肠孤病毒的存在刺激了人体自身的免疫系统,白细胞或“杀手”T细胞被吸引到肿瘤部位来攻击癌症。

此外,与对照组样本(接受了手术但未接受病毒治疗的患者组织样本)相比,注射呼肠孤病毒的患者组织具有更高水平的干扰素它的作用是启动机体的免疫系统);同时,呼肠孤病毒上调了干扰素调控的基因表达,包括肿瘤中的PD-1/PD-L1轴。随后,研究也证实,在临床前胶质瘤模型中,加入PD-1阻断疗法到呼肠孤病毒治疗中增强了全身性治疗。

领导该研究的英国利兹大学的医学肿瘤学家Adel Samson博士说:“这是首次发现,一种治疗性病毒能够通过血脑屏障。更重要的是,它不仅到达了大脑肿瘤处,还刺激了机体攻击癌症的免疫防御。这开启了一种可能性,即这种免疫疗法可以用于治疗更多患有侵袭性脑癌的患者。”


图片来源:利兹大学

研究人员还表示,呼肠孤病毒疗法能够用于与其他癌症疗法联合,使它们变得更有效。因为这种病毒只感染癌细胞,并不“打扰”健康细胞,并且,接受治疗的患者只报告了轻微的流感样(flu-like)副作用。

目前,科学家们正在调查这种病毒免疫疗法延长和改善脑肿瘤患者生活的有效性。在一项已经进行的临床试验中,患者接受了放疗、化疗、手术以及呼肠孤病毒的联合治疗。

主持该试验的论文共同通讯作者、利兹大学临床肿瘤学教授Susan Short说:“我们希望,病毒在增强机体对肿瘤的免疫响应方面能带来额外的作用,即,增加被标准治疗、放疗和化疗杀死的肿瘤细胞数量。”


图片来源:Science Translational Medicine

论文二:对抗乳腺癌

在另一篇题为“Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy”的论文中,来自渥太华医院和渥太华大学的研究者们证实,溶瘤病毒(Maraba)与另一种免疫疗法——检查点抑制剂——的联合能够更成功地治疗乳腺癌。

研究人员在模拟了术后乳腺癌转移扩散的小鼠模型中测试了这种联合疗法。在这些模型中,病毒治疗在手术前进行,检查点抑制剂治疗在手术后进行。结果显示,溶瘤病毒与检查点抑制剂的联合治愈了60%-90%的小鼠。

论文的共同通讯作者兼第一作者Marie-Claude Bourgeois-Daigneault博士说:“这绝对是惊人的。我们能够在大多数实验小鼠中治愈癌症,甚至是在通常非常抵抗免疫疗法的小鼠模型中。尽管需要进一步的研究进行测试,但我们相信,同样的机制也能在人类癌症中起作用。”

参考资料:

Virus could treat brain tumours by boosting immune system

Could viruses take cancer immunotherapy to the next level?

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

    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.

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

    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.

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