Neurotropic oncolytic viruses are appealing agents to treat brain tumors as they penetrate the blood–brain barrier and induce preferential cytolysis of neoplastic cells. The pathobiological similarities between human and canine brain tumors make immunocompetent dogs with naturally occurring tumors attractive models for the study of oncolytic virotherapies. In this dose-escalation/expansion study, an engineered Lasota NDV strain targeting the urokinase plasminogen activator system (rLAS-uPA) was administered by repetitive intravenous infusions to 20 dogs with intracranial tumors with the objectives of characterizing toxicities, immunologic responses, and neuroradiological anti-tumor effects of the virus for up to 6 months following treatment. Dose-limiting toxicities manifested as fever, hematologic, and neurological adverse events, and the maximum tolerated dose (MTD) of rLAS-uPA was 2 × 107pfu/mL. Mild adverse events, including transient infusion reactions, diarrhea, and fever were observed in 16/18 of dogs treated at or below MTD. No infectious virus was recoverable from body fluids. Neutralizing antibodies to rLAS-uPA were present in all dogs by 2 weeks post-treatment, and viral genetic material was detected in post-treatment tumors from six dogs. Tumor volumetric reductions occurred in 2/11 dogs receiving the MTD. Systemically administered rLAS-uPA NDV was safe and induced anti-tumor effects in canine brain tumors, although modifications to evade host anti-viral immunity are needed to optimize this novel therapy.
嗜神经溶瘤病毒因其能穿透血脑屏障并优先诱导肿瘤细胞溶解，成为治疗脑肿瘤的理想载体。人与犬类脑肿瘤在病理生物学上的相似性，使得具有免疫功能的自然发病犬成为研究溶瘤病毒疗法的理想模型。在本项剂量递增/扩展研究中，我们通过重复静脉输注方式，将靶向尿激酶纤溶酶原激活剂系统的基因工程拉斯塔新城疫病毒株（rLAS-uPA）应用于20只颅内肿瘤犬，旨在评估治疗后6个月内该病毒的毒性特征、免疫应答及神经影像学抗肿瘤效应。剂量限制性毒性表现为发热、血液学及神经系统不良事件，确定rLAS-uPA的最大耐受剂量为2×10⁷pfu/mL。在18只接受等于或低于最大耐受剂量治疗的犬中，16只出现轻度不良事件，包括短暂输注反应、腹泻和发热。所有体液样本均未检出感染性病毒。治疗后两周所有犬均出现rLAS-uPA中和抗体，并在6只犬的治疗后肿瘤组织中检测到病毒遗传物质。接受最大耐受剂量治疗的11只犬中，2只出现肿瘤体积缩小。全身给药的rLAS-uPA新城疫病毒在犬脑肿瘤治疗中表现出安全性并诱导抗肿瘤效应，但需通过规避宿主抗病毒免疫的策略优化该新型疗法。
肿瘤(癌症)患者之家