Departments of1Neurosurgery.
4Purdue University College of Veterinary Medicine, West Lafayette, Indiana.
Neurosurg Focus. 2021 Feb;50(2):E5. doi: 10.3171/2020.11.FOCUS20844.
The diagnosis of glioma remains disheartening in the clinical realm. While a multitude of studies and trials have shown promise, improvements in overall survival have been disappointing. Modeling these tumors in the laboratory setting has become increasingly challenging, given their complex in situ behavior and interactions for therapeutic evasion. Dogs, particularly brachycephalic breeds, are known to spontaneously develop gliomas that resemble human gliomas both clinically and pathophysiologically, making canines with sporadic tumors promising candidates for study. Typically, survival among these dogs is approximately 2 months with palliation alone.
The authors have completed the first stage of a unique phase I dose-escalating canine clinical trial in which the safety and tolerability of M032, a nonneurovirulent oncolytic herpes simplex virus-1 vector genetically engineered to express interleukin-12, are being studied in pet dogs with gliomas undergoing maximum safe tumor resection and inoculation of the cavity with the viral infusate.
Twenty-five canine patients were enrolled between January 2018 and August 2020. One patient was electively withdrawn from the trial by its owner, and 3 did not receive the virus. For the 21 dogs that remained, 13 had high-grade gliomas, 5 had low-grade gliomas, and 3 were undetermined. According to histopathological analysis, 62% of the tumors were oligodendrogliomas. At the time of this report, the median overall survival from the date of treatment was 151 days (± 78 days). No significant adverse events attributable to M032 or dose-limiting toxicities have been observed to date.
In this largest study of oncolytic viral therapy for canine brain tumors to date, treatment with M032 did not cause harm and the combination of surgery and oncolytic viral therapy may have contributed to prolonged survival in pet dogs with spontaneous gliomas. Forthcoming in-depth radiographic, immunohistochemical, and genetic analyses will afford a more advanced understanding of how this treatment impacts these tumors and the immune system. Our goal is to utilize these findings bitranslationally to inform human studies and refine therapies that will improve outcomes in both humans and pet dogs with gliomas.
在临床领域，脑肿瘤的诊断仍然令人沮丧。尽管大量的研究和试验显示出了希望，但总体生存率的提高却令人失望。由于其在原位的复杂行为和逃避治疗的相互作用，在实验室环境中对这些肿瘤进行建模变得越来越具有挑战性。众所周知，狗，特别是短头品种，会自发地患上与人类脑肿瘤在临床和病理生理学上都相似的脑肿瘤，因此患有散发性肿瘤的犬是很有前途的研究候选者。通常情况下，这些狗仅通过姑息治疗的存活期约为 2 个月。
作者完成了一项独特的 I 期剂量递增犬临床试验的第一阶段，该试验正在研究一种非神经毒性溶瘤单纯疱疹病毒-1 载体 M032，该载体经过基因工程改造后可表达白细胞介素-12，用于接受最大安全肿瘤切除并将病毒输注物接种到肿瘤腔中的患有脑肿瘤的宠物犬。
2018 年 1 月至 2020 年 8 月期间共纳入 25 例犬患者。1 例患者被其主人自愿退出试验，3 例未接受病毒治疗。对于其余 21 只狗，其中 13 只为高级别胶质瘤，5 只为低级别胶质瘤，3 只为未确定级别。根据组织病理学分析，62%的肿瘤为少突胶质细胞瘤。截至本报告时，自治疗之日起的中位总生存期为 151 天（±78 天）。迄今为止，尚未观察到与 M032 相关或剂量限制毒性的任何重大不良事件。
在迄今为止最大的犬脑肿瘤溶瘤病毒治疗研究中，M032 治疗并未造成伤害，手术联合溶瘤病毒治疗可能延长了自发性脑肿瘤犬的生存时间。即将进行的深入影像学、免疫组织化学和遗传分析将使我们更深入地了解这种治疗方法如何影响这些肿瘤和免疫系统。我们的目标是利用这些发现双向转化，为人类研究提供信息，并改进治疗方法，以提高人类和患有脑肿瘤的犬的治疗效果。
