Systemic Therapy with Infectivity-Selective Oncolytic Adenovirus for PDAC

感染性选择性溶瘤腺病毒对 PDAC 的全身治疗

• 批准号: 9199848
• 负责人: MASATO YAMAMOTO
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-04 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199848
• 关键词: Adenoviruses; Advanced Malignant Neoplasm; Affinity; Amino Acids; Binding; Binding Proteins; Biological; Cancer Etiology; Cells; Cellular Immunity; Cessation of life; Clinical; Data; Development; Diagnosis; Diagnostic; Disease; Excision; Exhibits; Fiber; Goals; Human; In Vitro; Infection; Injectable; Injection of therapeutic agent; Kupffer Cells; Lead; Legal patent; Libraries; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methods; Modality; Modeling; Modification; Neoplasm Metastasis; Normal Cell; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Organ; Outcome; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Performance; Property; Proteins; Refractory; Role; Scheme; Surface; Surface Plasmon Resonance; System; Systemic Therapy; Testing; Therapeutic; Therapeutic Effect; Unresectable; Viral; Virion; Virus; Virus Replication; Xenograft Model; advanced disease; antitumor effect; base; cancer cell; chemotherapy; clinical application; clinical development; clinical effect; clinically relevant; dosage; experience; high throughput screening; improved; in vivo; inhaled nitric oxide; intravenous administration; intravenous injection; mesothelin; neutralizing antibody; novel; novel therapeutics; oncolysis; pre-clinical; promoter; public health relevance; screening; subcutaneous; tumor; vector; virology

 DESCRIPTION (provided by applicant): Pancreatic Ductal Adenocarcinoma (PDAC) is still a devastating disease that ranks as the fourth leading cause of cancer related death, and its five-year survival remains around 6%. Currently, most PDAC patients are diagnosed with spread or metastasized diseases. In order to change this dismal clinical outcome, the development of novel systemic treatment of locally-spread and metastatic lesions is in need. Oncolytic virus represents one such potential therapeutic modality, and adenovirus (Ad) is a strong candidate because of its efficient in vivo transduction mediated by specific protein-to-protein binding and the exponential replication causing oncolysis. However, even oncolytic adenoviruses (OAds) with the highest infectivity have not yet achieved efficient therapeutic effect upon systemic administration because of non-selective distribution and sequestration by non-target organs. Targeting at the level of viral binding/infection therefore has strong advantages for realizing systemic treatment of advanced cancers. The incorporation of pre-identified ligands in Ad virion has been heavily tried, but inhibition of viral replication or loss of ligand affinity has hampered the realization of the vector in most cases. To overcome this issue, we recently developed a novel ligand for transductional targeting by screening large diversity targeting ligand library (1010 order) in adenovirus format and identified a novel targeting ligand (VTINRSA) against mesothelin (MSLN) that is expressed on the surface of many PDACs. The oncolytic adenovirus (OAd) with this motif (VTIN-OAd) achieved targeted binding and replication in MSLN-expressing cells in vitro as well as selective replication and antitumor effects after intratumoral injection n vivo. The intravenous injection showed significantly lower liver sequestration and better tumor accumulation. More importantly, its intravenous injection exhibited strong antitumor effects in a PDAC subcutaneous xenograft model, even at a low dosage (3x109 vp). The infectivity-selective OAd possesses key properties to embody systemic treatment of pancreatic cancers and thus gives us a unique opportunity to develop novel pancreatic cancer therapeutics that are systemically injectable. The overarching goal of this project is to bring this promising vector ino the clinical stage. The biological/virological backgrounds of the improvement of viral performance upon systemic therapy will be elucidated in vitro and in vivo. We will construct and validate the clinically applicable OAd with this new targeting strategy for systemic therapy of pancreatic cancer. We will also pursue further enhancement of the anti-tumor effect by combining them with chemotherapy. The rigorous tests planned in this proposal will determine the lead OAd and the optimal administration scheme in patients. Successful clinical development of the potent and systemically-injectable oncolytic Ad-based therapy has a high potential to improve the clinical outcome of the patients with unresectable PDAC and other refractory cancers.

 描述(申请人提供)：胰腺导管腺癌(PDAC)仍然是一种毁灭性的疾病，是癌症相关死亡的第四大原因，其五年生存率保持在6%左右。目前，大多数PDAC患者被诊断为播散性或转移性疾病。为了改变这一令人沮丧的临床结果，需要开发新的系统治疗局部扩散和转移的病变。溶瘤病毒代表了一种潜在的治疗方式，而腺病毒(Ad)是一种强有力的候选方案，因为它通过特异的蛋白结合介导体内有效的转导，以及引起肿瘤溶解的指数复制。然而，由于非靶器官的非选择性分布和隔离，即使是感染性最强的溶瘤腺病毒(OAD)，在全身给药时也没有取得有效的治疗效果。因此，以病毒结合/感染水平为靶点对于实现晚期癌症的系统治疗具有强大的优势。在AdVirion中加入预先识别的配体已经进行了大量的尝试，但抑制病毒复制或失去配体亲和力阻碍了这种尝试 大多数情况下向量的实现。为了解决这个问题，我们最近通过筛选腺病毒形式的大多样性靶向配体文库(1010个序列)，开发了一种新的转导靶向配体，并鉴定了一种新的靶向配体(VTINRSA)，该配体针对许多PDAC表面表达的间充质蛋白(MSLN)。带有该基序的溶瘤腺病毒(OAD)在体外可在表达MSLN的细胞中实现靶向结合和复制，体内注射后可获得选择性复制和抗肿瘤作用。静脉注射组的肝隔离度显著降低，肿瘤积聚明显改善。更重要的是，它的静脉注射在PDAC皮下移植模型中表现出很强的抗肿瘤作用，即使在低剂量(3x109 VP)下也是如此。感染性选择性的OAD具有体现胰腺癌系统治疗的关键特性，从而为我们提供了一个独特的机会来开发可系统注射的新型胰腺癌治疗方法。该项目的首要目标是将这种有希望的载体带入临床阶段。系统治疗后病毒性能改善的生物学/病毒学背景将在体外和体内阐明。我们将利用这一新的靶向策略构建并验证临床适用的OAD，用于胰腺癌的系统治疗。我们还将寻求通过将它们与化疗相结合来进一步增强抗肿瘤作用。该提案中计划的严格测试将确定患者的主要OAD和最佳给药方案。这种有效的、可系统注射的基于Ad的溶瘤疗法的成功临床开发，对改善不能切除的PDAC和其他难治性癌症的患者的临床预后具有很高的潜力。