PO.IM01.10 · 免疫学

IDH1-R132H通过促进病毒进入和免疫激活增强溶瘤HSV-1对胶质瘤的治疗

IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma

编号 1547 展板 1 时间 4/20 09:00–12:00 区域 Section 8 主讲 Eleni Panagioti, D Phil

分会场 Combination Immunotherapies

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作者与单位 Authors & Affiliations

Eleni Panagioti¹, Hunter J. Kelley², Alexander L. Ling², William Goins³, Daniel Roberts¹, Sotiris Sotiriou⁴, Bryan J. Iorgulescu⁵, Karen Dixon⁶, Michael B. Yaffe⁷, Maria G. Castro⁸, Sean E. Lawler⁹, Gordon J. Freeman¹⁰, Vijay K. Kuchroo¹¹, E Antonio Chiocca¹², Charles H. Cook¹

¹Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA,²Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA,³Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA,⁴Department of Pathology, Aristotle University of Thessaloniki, Thessaloniki, Greece,⁵Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX,⁶Department of Biomedicine, University of Basel, Basel, Switzerland,⁷Department of Biological Engineering, Massachusetts Institute of Technology, Boston, MA,⁸Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI,⁹Department of Pathology and Laboratory Medicine, Brown University, Providence, RI,¹⁰Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA,¹¹Department of Neurology, Brigham and Women's Hospital, Boston, MA,¹²Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA

摘要 Abstract

中文摘要

溶瘤病毒疗法代表了一条有前景但尚未充分探索的精准癌症治疗途径，尤其是在针对肿瘤特异性分子改变进行定制时。高级别IDH突变型星形细胞瘤患者仍面临治疗选择有限和预后不良，凸显了对新策略的需求。本研究中，我们评估了rQNestin34.5v.2——一种工程化溶瘤HSV-1——在IDH1-R132H突变型高级别弥漫性胶质瘤中的治疗潜力。我们证明IDH1-R132H突变通过上调Nectin-1（胶质瘤中HSV-1的主要进入受体）增加胶质瘤对病毒感染的易感性。同时，IDH1-R132H驱动的DNA高甲基化抑制干扰素（IFN）信号（一条必需的抗病毒防御通路），创造了一个允许增强病毒复制并增加肿瘤细胞对病毒诱导凋亡敏感性的环境。在免疫健全的IDH1-R132H小鼠胶质瘤模型中，瘤内递送rQNestin34.5v.2诱导了强烈的免疫激活，表现为肿瘤内免疫细胞浸润增加和IFN-gamma的全身释放。然而，肿瘤浸润淋巴细胞上脊髓灰质炎病毒受体（PVR-CD155）和抑制性免疫检查点T细胞免疫球蛋白与ITIM结构域受体（TIGIT）的表达升高，提示病毒治疗后出现适应性耐药机制。将rQNestin34.5v.2与TIGIT阻断联合相比单药治疗增强了疗效并改善了生存结局。总之，这些数据表明IDH1-R132H重塑了病毒进入通路和抗病毒免疫防御，将其确立为溶瘤病毒治疗反应的预测性生物标志物。

查看英文原文 English abstract

Oncolytic virotherapy represents a promising yet under-explored therapeutic avenue for precision cancer treatment, particularly when tailored to tumor-specific molecular alterations. Patients with high-grade IDH-mutant astrocytomas continue to face limited treatment options and poor outcomes, emphasizing the need for novel strategies. In this study, we evaluated the therapeutic potential of rQNestin34.5v.2, an engineered oncolytic HSV-1, in the context of IDH1-R132H-mutant high-grade diffuse gliomas. We show that the IDH1-R132H mutation increases glioma susceptibility to viral infection by upregulating Nectin-1, the main HSV-1 entry receptor in gliomas. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, an essential antiviral defense pathway, creating a permissive environment that supports enhanced viral replication and increases tumor cell sensitivity to virus-induced apoptosis. In immunocompetent IDH1-R132H murine glioma models, intratumoral delivery of rQNestin34.5v.2 induced robust immune activation, marked by increased immune-cell infiltration into the tumor and systemic release of IFN-gamma. However, elevated expression of poliovirus receptor (PVR-CD155) and the inhibitory immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating lymphocytes, suggested the emergence of an adaptive resistance mechanism following virotherapy. Combining rQNestin34.5v.2 with TIGIT blockade enhanced therapeutic efficacy and improved survival outcomes compared to monotherapy. Collectively, these data demonstrate that IDH1-R132H reshapes both viral entry pathways and antiviral immune defenses, identifying it as a predictive biomarker for oncolytic virotherapy response.

利益披露 Disclosure

E. Panagioti, None.. H. Kelley, None.. A. L. Ling, None.. W. Goins, None.. D. Roberts, None.. S. Sotiriou, None.. B. Iorgulescu, None.. K. Dixon, None.. M. Yaffe, None.. M. G. Castro, None.. S. E. Lawler, None. G. J. Freeman, Roche Other Intellectual Property. Merck MSD Patent. AstraZeneca Patent. Bristol-Myers-Squibb Patent. Merck KGA Patent. Boehringer-Ingelheim Patent. Dako Patent. Leica Patent. Mayo Clinic Patent. Eli Lilly Patent. Coherus BioSciences Patent. Novartis Patent. Nextpoint Stock. ,iTeos Stock. IgM Stock. Invaria Stock. GV20 Stock. Bioentre Stock. Geode Stock. V. Kuchroo, Tizona Stock. Trishula Therapeutics Stock. Celsius Therapeutics Stock. Bicara Therapeutics Stock. Larkspur Therapeutics Stock. Werewolf Therapeutics Stock. Biocon Biologic Stock Option. Compass Stock Option. Elpiscience Biopharmaceutical Stock Option. Equilium Stock Option. PerkinElmer Stock Option. Syngene Stock Option. Cell Signaling Technology Advisor. Elpiscience Biopharmaceutical Advisor. Tr1X Advisor. Werewolf Advisor. Tizona Therapeutics Advisor. E. Chiocca, to Bionaut Labs Advisor. Seneca Therapeutics Advisor. ReIgnite Advisor. Calidi Advisor. Ternalys Therapeutics g., Board of Directors, non-salaried role). Candel Therapeutics, Inc Other Intellectual Property. C. Cook, None.

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