Advanced Oncolytic Adenovirus Enabling Systemic Therapy of PDAC

先进的溶瘤腺病毒实现 PDAC 的系统治疗

基本信息

批准号：
10566530
负责人：
MASATO YAMAMOTO
金额：
$ 35.46万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-12 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566530
关键词：
Adenovirus Infections Adenovirus Vector Adenoviruses Adoptive Transfer Adverse effects Antineoplastic Agents Area Binding Characteristics Clinic Visits Clinical Development Diagnosis Erythrocytes Fiber Generations Goals Hamsters Hemagglutination Human Immunize Immunosuppression In Vitro Infection Injectable Injections Libraries Liver Lung Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Mus Neoplasm Metastasis Oncolytic viruses Operative Surgical Procedures Organ Outcome PTGS2 gene Pancreas Pancreatic Ductal Adenocarcinoma Patients Process Prognosis Proteins Refractory Reporting Series Serology Seroprevalences Serum Specificity Subgroup Surface Survival Rate System Systemic Therapy Testing Therapeutic Therapeutic Effect Thrombosis Time Toxic effect Tropism Tumor Antigens Tumor stage Vertebral column Viral Virus Xenograft Model advanced disease antitumor effect cancer cell chemotherapy clinically relevant conditionally replicative adenovirus design high throughput screening immunogenic cell death improved in vivo in vivo Model in vivo evaluation mesothelin neutralizing antibody novel novel strategies oncolysis oncolytic adenovirus pancreatic cancer cells pancreatic ductal adenocarcinoma cell promoter tumor

Adenovirus Infections Adenovirus Vector Adenoviruses Adoptive Transfer Adverse effects Antineoplastic Agents Area Binding Characteristics Clinic Visits Clinical Development Diagnosis Erythrocytes Fiber Generations Goals Hamsters Hemagglutination Human Immunize Immunosuppression In Vitro Infection Injectable Injections Libraries Liver Lung Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Mus Neoplasm Metastasis Oncolytic viruses Operative Surgical Procedures Organ Outcome PTGS2 gene Pancreas Pancreatic Ductal Adenocarcinoma Patients Process Prognosis Proteins Refractory Reporting Series Serology Seroprevalences Serum Specificity Subgroup Surface Survival Rate System Systemic Therapy Testing Therapeutic Therapeutic Effect Thrombosis Time Toxic effect Tropism Tumor Antigens Tumor stage Vertebral column Viral Virus Xenograft Model advanced disease antitumor effect cancer cell chemotherapy clinically relevant conditionally replicative adenovirus design high throughput screening immunogenic cell death improved in vivo in vivo Model in vivo evaluation mesothelin neutralizing antibody novel novel strategies oncolysis oncolytic adenovirus pancreatic cancer cells pancreatic ductal adenocarcinoma cell promoter tumor

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项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and refractory malignancy, whose five-year survival rate remains only 9%. Less than 20% of the patients visiting clinics are candidates for surgery because most PDAC patients have advanced diseases at the time of diagnosis. The majority of PDAC patients therefore require systemic therapies. While there is promising advance in cancer therapeutics, their median survival is < 6 months. These PDAC patients need development of new approaches for systemic treatment. Oncolytic viruses are promising anti-cancer agents under development. Among them, oncolytic adenovirus (OAd) is one of the strong candidates. Despite needs of systemic treatments for PDAC, the vast majority of OAds are designed for local administration due to several obstacles, such as sequestration to normal organs, difficulty for selective delivery to the tumor, neutralizing antibodies, and hemagglutination. Aiming at development of an OAd enabling treatment of advanced PDAC patients by systemic injection, we will tackle these obstacles in this project. Adenoviruses have more than 50 serologically defined types, and this is a unique feature enabling escape from neutralizing Abs. However, simple switching the backbone has not realized cancer specificity because tropisms of adenoviruses are not cancer specific. We previously identified mesothelin (MSLN)-targeted OAd for PDAC treatment and reported the feasibility of knob switch. We will generate a new series of OAds based on a variety of Ad species other than Ad5, where the fiber-knob regions are replaced by the knob with pancreatic cancer-specific binding motif in the original binding domain (AB-loop). We hypothesize that these viruses will allow selective delivery to the tumor by systemic injection while avoiding the effect of nAbs and hemagglutination. This project is expected to overcome the current and potential issues of systemic therapy of PDAC with oncolytic virus by exploiting the advantages of the adenoviral vector system and our unique advantages in adenovirus targeting strategies. The potential impact of systemically injectable OAd for PDAC is significant.

胰腺导管腺癌（PDAC）是一种侵略性和难治性恶性肿瘤，其五年生存率仍然只有9％。不到20％的患者参观诊所候选手术，因为大多数PDAC患者在诊断。因此，大多数PDAC患者需要全身疗法。而有在癌症治疗方面有希望的进步，其中位生存期为6个月。这些PDAC 患者需要开发新方法进行全身治疗。溶瘤病毒是正在开发的有希望的抗癌药物。他们之中，溶瘤腺病毒（OAD）是强大的候选者之一。尽管需要全身治疗对于PDAC，由于几个障碍物，例如隔离到正常器官，很难选择性地递送到肿瘤，中和抗体和血凝。旨在通过全身性开发OAD，以实现晚期PDAC患者的治疗注射，我们将解决该项目中的这些障碍。腺病毒有超过50 血清学定义的类型，这是一个独特的特征，可从中和ABS中逃脱。但是，简单切换主链并未意识到癌症特异性，因为腺病毒不是特定于癌症的。我们先前鉴定了间皮素（MSLN）靶向的OAD 用于PDAC处理并报告了旋钮开关的可行性。我们将生成一系列新的基于AD5以外的各种AD物种的OAD，更换纤维旋钮区域由原始结合结构域（AB-loop）中的胰腺癌特异性结合基序的旋钮。我们假设这些病毒将允许通过全身注射选择性地传递到肿瘤同时避免NAB和血凝的作用。预计该项目将克服当前和潜在的系统治疗问题通过利用腺病毒媒介系统的优势和我们腺病毒靶向策略的独特优势。系统上的潜在影响 PDAC的可注射OAD很重要。