西班牙纳瓦拉健康研究所Marta M. Alonso团队研究了溶瘤DNX-2401病毒治疗小儿弥漫性内生性桥脑胶质瘤的疗效。相关论文发表在2022年6月29日出版的《新英格兰医学杂志》上。

弥漫性内生性桥脑胶质瘤（DIPG）患儿预后不良，中位生存期不到1年。溶瘤病毒治疗已用于治疗脑其他部位的儿童胶质瘤患者，但缺乏关于DIPG患者溶瘤病毒治疗的数据。

研究组对DNX-2401进行了一项单中心剂量递增研究，DNX-2401是一种在新诊断DIPG患者的肿瘤细胞中选择性复制的溶瘤腺病毒。患者通过放置在小脑脚的导管接受单次病毒输注，然后进行放射治疗。

主要目标是评估DNX-2401的安全性和不良事件概况。次要目标是评估DNX-2401对总体生存率和生活质量的影响，确定有客观缓解的患者百分比，并收集肿瘤活检和外周血样本，以进行DIPG分子特征和抗肿瘤免疫反应的相关研究。

共有12名3至18岁的新诊断DIPG患者接受了1×10¹⁰（前4名患者）或5×10¹⁰（后8名患者）DNX-2401病毒颗粒治疗，11名患者接受了后续放疗。患者的不良反应包括头痛、恶心、呕吐和疲劳。偏瘫和四肢瘫痪各1例。

在17.8个月的中位随访期间，据磁共振成像评估，9名患者的肿瘤尺寸缩小，3名患者部分缓解，8名患者病情稳定。中位生存期为17.8个月。两名患者在撰写本报告时仍然存活，其中一名患者在38个月时没有肿瘤进展。对1名患者尸检期间获得的肿瘤样本和外周血研究表明，肿瘤微环境和T细胞库发生了改变。

研究结果表明，DIPG患儿肿瘤内输注溶瘤病毒DNX-2401，然后进行放射治疗，可导致部分患者的T细胞活性改变，肿瘤大小缩小或稳定，但与不良事件有关。

附：英文原文

Title: Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma

Author: Jaime Gállego Pérez-Larraya, M.D., Ph.D.,, Marc Garcia-Moure, Ph.D.,, Sara Labiano, Ph.D.,, Ana Patio-García, Ph.D.,, Jessica Dobbs, Ph.D.,, Marisol Gonzalez-Huarriz, Ph.D.,, Marta Zalacain, Ph.D.,, Lucia Marrodan, B.S.,, Naiara Martinez-Velez, Ph.D.,, Montserrat Puigdelloses, Ph.D.,, Virginia Laspidea, M.S.,, Itziar Astigarraga, M.D.,, Blanca Lopez-Ibor, M.D.,, Ofelia Cruz, M.D.,, Miren Oscoz Lizarbe, M.D.,, Sandra Hervas-Stubbs, Ph.D.,, Gorka Alkorta-Aranburu, Ph.D.,, Ibon Tamayo, Ph.D.,, Beatriz Tavira, Ph.D.,, Ruben Hernandez-Alcoceba, M.D., Ph.D.,, Chris Jones, Ph.D.,, Gitanjali Dharmadhikari, M.S.,, Cristian Ruiz-Moreno, Ph.D.,, Henk Stunnenberg, Ph.D.,, Esther Hulleman, Ph.D.,, Jasper van der Lugt, M.D., Ph.D.,, Miguel á. Idoate, M.D.,, Ricardo Diez-Valle, M.D., Ph.D.,, Inés Esparragosa Vázquez, M.D.,, Maria Villalba, Ph.D.,, Carlos de Andrea, M.D., Ph.D.,, Jorge M. Núez-Córdoba, M.D.,, Brett Ewald, Ph.D.,, Joan Robbins, Ph.D.,, Juan Fueyo, M.D., Ph.D.,, Candelaria Gomez-Manzano, M.D., Ph.D.,, Frederick F. Lang, M.D.,, Sonia Tejada, M.D., Ph.D.,, and Marta M. Alonso, Ph.D.

Issue&Volume: 2022-06-29

Abstract:

Background

Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking.

Methods

We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses.

Results

A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire.

Conclusions

Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events.

DOI: 10.1056/NEJMoa2202028

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2202028