Intravenous Administration of Vesicular Stomatitis Vectors

水泡性口炎载体的静脉注射

• 批准号: 9071379
• 负责人: KAH-WHYE PENG
• 金额: $ 33.61万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-19 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071379
• 关键词: Acute; Acute Liver Failure; Address; Adenoviruses; Animals; Antibodies; Area; Attenuated; Blood; Blood Volume; Body Surface Area; Body Weight; Cancer Patient; Canis familiaris; Cells; Clinical; Data; Databases; Dose; Dose-Limiting; Enzymes; Exhibits; Health; Hepatic; Hepatocyte; Hepatotoxicity; Hour; Human; Immunocompetent; Infection; Inflammatory; Inflammatory Response; Infusion procedures; Interferon-beta; Interferons; Interleukin-12; Interleukin-6; Intravenous; Intravenous infusion procedures; Investigation; Kupffer Cells; Life; Liver; Liver Function Tests; Malignant Neoplasms; Metabolic; Modeling; Monitor; Multiple Myeloma; Mus; No-Observed-Adverse-Effect Level; Oncolytic viruses; Oryctolagus cuniculus; Plasma; Preparation; Published Comment; Rattus; Recombinants; Refractory; Relapse; Rosa; Safety; Schedule; Serum; Spleen; Stomatitis; Surface; Systemic Therapy; TNF gene; Testing; Toxic effect; Toxicology; Translations; Vesicular stomatitis Indiana virus; Viral; Viral Vector; Virion; Virus; Virus Activation; Virus Diseases; Weight; Xenograft procedure; acute toxicity; base; cancer therapy; companion animal; cytokine; design; human subject; intravenous administration; macrophage; mouse model; neurotoxicity; novel strategies; oncolytic Vesicular Stomatitis Virus; oncolytic virotherapy; particle; preclinical study; tumor; vector

DESCRIPTION (provided by applicant): Oncolytic Vesicular Stomatitis Virus (VSV) has potent antitumor activity against multiple myeloma. Safety concerns regarding VSV-induced neurotoxicity have largely been addressed by vector design; these recombinant VSV demonstrate tumor selectivity, attenuated neurotoxicity and potent antitumor activities against syngeneic and xenogeneic tumors. In recent preclinical studies evaluating the efficacy and safety of a new recombinant VSV for intravenous myeloma therapy, we discovered significant acute toxicities associated with high dose intravenous administration of VSV. No clinical signs of neurotoxicity were seen. Instead, animals given high dose VSV intravenously exhibited signs of acute hepatotoxicity. The finding of acute hepatic dose-limiting toxicity of intravenously administered oncolytic VSV in two animal species is of major significance for the oncolytic virotherapy field and raises important translational questions. First, it is currently unclear whether the liver toxicity is caused by the physical virus particles (in which case doses should be calibrated to this parameter) or is a consequence of cell infection. Second it is currently unknown whether toxicity will be more or less severe in the presence of circulating anti-VSV antibodies. Third, it will be important to determine whether the toxicity can be ameliorated by modifying the schedule of virus administration, for example by slowing the infusion rate or by pre-dosing with a lower dose of virus, which has been proven effective in the case of adenovirus particles. Fourth, it is currently unknown whether allometric scaling of virus dosing between species should be on the basis of body weight or surface area. The generally accepted view is that it should be based on weight which tracks with blood volume and hence with maximum circulating virus concentration after intravenous infusion. However, our preliminary data suggests that this accepted viewpoint is wrong and that allometric scaling of virus dose should be on the basis of surface area. To address these questions, we propose to 1) define the mechanistic basis for acute hepatotoxicity after intravenous administration of VSV in mice, 2) determine whether interspecies allometric scaling of the oncolytic virus dose should be on the basis of body weight or surface area. 3) determine whether virus predosing ameliorates the acute hepatic toxicity of VSV.

描述（由申请人提供）：溶瘤性水疱性口炎病毒（VSV）对多发性骨髓瘤具有有效的抗肿瘤活性。关于vsv诱导的神经毒性的安全问题已在很大程度上通过媒介设计得到解决；这些重组VSV表现出肿瘤选择性、减弱的神经毒性和对同质和异种肿瘤的有效抗肿瘤活性。在最近的临床前研究中，评估了一种新的重组VSV静脉注射治疗骨髓瘤的有效性和安全性，我们发现高剂量静脉注射VSV有明显的急性毒性。未见神经毒性的临床症状。相反，静脉注射高剂量VSV的动物表现出急性肝毒性的迹象。静脉给药溶瘤VSV在两种动物体内的急性肝剂量限制性毒性的发现对溶瘤病毒治疗领域具有重要意义，并提出了重要的转化问题。首先，目前尚不清楚肝毒性是由物理病毒颗粒引起的（在这种情况下，剂量应校准为该参数）还是细胞感染的结果。其次，目前尚不清楚存在循环中的抗vsv抗体时毒性是否更严重或更轻。第三，重要的是确定是否可以通过改变病毒给药的时间表来改善毒性，例如通过减慢输注速度或预先注射较低剂量的病毒，这已被证明对腺病毒颗粒有效。第四，目前尚不清楚物种间病毒剂量的异速计量应以体重为基础还是以表面积为基础。普遍接受的观点是，应以体重为基础，体重与血容量密切相关，因此与静脉输注后最大循环病毒浓度密切相关。然而，我们的初步数据表明，这种公认的观点是错误的，病毒剂量的异速缩放应该以表面积为基础。为了解决这些问题，我们建议1)确定小鼠静脉注射VSV后急性肝毒性的机制基础，2)确定溶瘤病毒剂量的种间异速计量是否应该基于体重或表面积。3)确定病毒预给药是否能改善VSV的急性肝毒性。