Advanced Oncolytic Adenovirus Enabling Systemic Therapy of PDAC

先进的溶瘤腺病毒实现 PDAC 的系统治疗

• 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
• 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

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)是一种侵袭性和难治性的恶性肿瘤， 其五年存活率仍然只有9%。去诊所就诊的患者中只有不到20%的人 因为大多数PDAC患者在接受手术时都患有晚期疾病 诊断。因此，大多数PDAC患者需要系统的治疗。趁有机会 在癌症治疗方面有希望取得进展，他们的中位生存期为&lt；6个月。这些PDAC 患者需要开发新的系统治疗方法。 溶瘤病毒是正在开发的很有前途的抗癌药物。其中， 溶瘤腺病毒(OAD)是一种强有力的候选病毒。尽管需要系统的治疗 对于PDAC，绝大多数OAD是为本地管理而设计的，因为有几个 障碍，如对正常器官的隔离，对肿瘤的选择性输送困难， 中和抗体和血凝。 旨在开发OAD使能治疗晚期PDAC患者的系统 注资后，我们将在这个项目中解决这些障碍。腺病毒有50多种 血清学定义的类型，这是一个独特的特征，使逃避中和抗体。 然而，简单地交换脊椎并没有实现癌症的特异性，因为 腺病毒不是癌症特异性的。我们之前发现了以间甲内酯(MSLN)为靶点的OAD 用于PDAC治疗，并报告了旋钮开关的可行性。我们将生成一系列新的 基于除Ad5以外的各种Ad物种的OAD，其中纤维结节区域被替换 通过在原始结合域(AB-环)中具有胰腺癌特异性结合基序的旋钮。 我们推测，这些病毒将允许通过全身注射选择性地输送到肿瘤。 同时避免了NaBS和血凝的影响。 这个项目预计将克服目前和潜在的系统治疗的问题 利用腺病毒载体系统和我们的 在腺病毒靶向策略方面具有独特的优势。系统性的潜在影响 可注射的OAD对PDAC具有重要意义。