Intravenous Administration of Vesicular Stomatitis Vectors

水泡性口炎载体的静脉注射

• 批准号: 8875637
• 负责人: KAH-WHYE PENG
• 金额: $ 35.27万
• 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/8875637
• 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; 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; Virotherapy; Virus; Virus Activation; Virus Diseases; Weight; Xenograft procedure; base; cancer therapy; companion animal; cytokine; design; human subject; intravenous administration; macrophage; mouse model; neurotoxicity; novel strategies; oncolytic Vesicular Stomatitis Virus; 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（由申请方提供）：溶瘤性水泡性口炎病毒（VSV）对多发性骨髓瘤具有强效抗肿瘤活性。关于VSV诱导的神经毒性的安全性问题已在很大程度上通过载体设计得到解决;这些重组VSV表现出肿瘤选择性、减弱的神经毒性和针对同基因和异种肿瘤的强效抗肿瘤活性。在最近的临床前研究中，评价了一种新的重组VSV用于静脉内骨髓瘤治疗的有效性和安全性，我们发现了与高剂量VSV静脉内给药相关的显著急性毒性。未观察到神经毒性的临床体征。相反，静脉给予高剂量VSV的动物表现出急性肝毒性体征。在两种动物种属中发现静脉给药溶瘤VSV的急性肝脏剂量限制性毒性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，剂量应根据该参数校准）还是细胞感染的结果。其次，目前尚不清楚在存在循环抗VSV抗体的情况下毒性是否会更严重或更轻。第三，重要的是确定是否可以通过改变病毒施用的时间表来改善毒性，例如通过减慢输注速率或通过预先给予较低剂量的病毒，这在腺病毒颗粒的情况下已被证明是有效的。第四，目前尚不清楚物种之间病毒剂量的异速生长比例是否应基于体重或表面积。普遍接受的观点是，它应该基于体重，体重与血容量有关，因此与静脉输注后的最大循环病毒浓度有关。然而，我们的初步数据表明，这种公认的观点是错误的，病毒剂量的异速生长比例应基于表面积。为了解决这些问题，我们建议1）定义小鼠静脉注射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生长比例是否应基于体重或表面积。3)确定病毒预给药是否改善VSV的急性肝毒性。