Enhancing Efficacy of Oncolytic Viriotherapy with PDT

通过 PDT 增强溶瘤病毒疗法的疗效

• 批准号: 8017410
• 负责人: Danuta B Kozbor
• 金额: $ 23.82万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017410
• 关键词: ABCG2 gene; Ablation; Affect; Antitumor Response; Beds; Blood Vessels; Buffaloes; Carbohydrates; Carcinoma; Cities; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Disease; Exhibits; Generations; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Histologic; Human; Hypoxia; Induction of Apoptosis; Kinetics; Lesion; Mediating; Modality; Morphology; Mus; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Patients; Phase; Phenotype; Photochemotherapy; Photosensitizing Agents; Primary Neoplasm; Procedures; Recombinants; Regimen; Relative (related person); Reporting; Roswell Park Cancer Institute; Sampling; Singlet Oxygen; Site; Solid Neoplasm; Structure; Time; Tissues; Tumor Tissue; Tumor Volume; Vaccinia virus; Vascular Permeabilities; Viral Vector; Virus; Virus Replication; Visible Radiation; Xenograft Model; Xenograft procedure; absorption; cell stroma; chemotherapy; cytotoxic; established cell line; immunodeficient mouse model; improved; neoplastic cell; preclinical study; public health relevance; pyropheophorbide a; response; trend; tumor; uptake; vector

DESCRIPTION (provided by applicant): Enhancing Efficacy of Oncolytic Virotherapy with PDT Preclinical and clinical studies using oncolytic viruses show promise for treating solid tumors. However, systemic delivery of oncolytic viral vectors to tumors is limited by an ineffective entry of the vector to the target site. We propose to explore the potential of oncolytic virotherapy used in combination with photodynamic therapy (PDT) for the treatment of head and neck tumors, for which PDT is an excellent modality. PDT uses activation of tumor localizing photosensitizer (PS) by visible light, and through generation of cytotoxic singlet oxygen induces damage to tumor cells. At Roswell Park Cancer Institute, the PDT group has identified a highly promising PS (HPPH), which is currently in Phase I/II clinical trials. To explore the potential of combination PDT and virotherapy in head and neck squamous cell carcinoma (HNSCC), we propose to investigate the effect of PDT-induced local tumor damage and changes in vascular permeability on the antitumor efficacy of virotherapy treatment in a xenograft model in mice. We found that while a recombinant oncolytic vaccinia virus (rOVV) alone had an impact on reducing tumor volume over time, the combined treatment with the optimally curative PDT regimen improved the antitumor response and tumor-free survival. We hypothesize that optimal PDT treatment conditions resulting in increases in vascular permeability will enhance the uptake and replication of rOVV in tumor tissues leading to ablation of primary tumor and long-term control of disseminated disease. Here, we propose to optimize the rOVV and PDT treatments alone and in combination, and to elucidate the mechanisms of PDT-mediated enhancement of rOVV virotherapy in xenografted HNSCC human tumors. The Specific Aims are: i) We will analyze the extent of histologic structure and vascular differences between SCC xenografts affects rOVV replication in the tumor lesions; ii) Using HPPH and its carbohydrate conjugate (HPPH-Gal), we will investigate the effect of tumor morphology, vascularity and the presence or absence of ABCG2 transporter on efficacy of the PDT treatment; iii) We will explore the kinetics of the rOVV delivery relative to PDT to maximize the benefit of combining the two treatments. PDT results in vascular leakiness and local tumor damage but how the degree of the local tissue response following PDT affects uptake of oncolytic viruses is unknown. These two procedures have different mechanisms of action and there could be an added benefit to combining the two treatments. PERFORMANCE SITE(S) (organization, city, state) Roswell Park Cancer Institute Elm & Carlton Streets Buffalo, NY 14263 PUBLIC HEALTH RELEVANCE: Enhancing Efficacy of Oncolytic Virotherapy with PDT We propose to investigate the effect of photodynamic therapy (PDT)-induced local tumor damage and changes in vascular permeability on the antitumor efficacy of oncolytic virotherapy treatment using xenografts of human head and neck squamous cell carcinomas (HNSCCs) in an immunodeficient mouse model. We hypothesize that optimal PDT treatment conditions resulting in increases in vascular permeability will enhance the uptake and replication of an oncolytic vaccinia virus in tumor tissues leading to ablation of primary tumor and long-term control of disseminated disease.

描述（由申请人提供）：使用溶瘤病毒通过PDT临床前和临床研究增强溶瘤病毒疗法的功效显示出对治疗实体瘤的有望。然而，全身性溶瘤病毒向量向肿瘤的递送受到载体无效进入目标部位的限制。我们建议探索与光动力疗法（PDT）相结合用于治疗头颈部肿瘤的潜力，PDT是一种极好的方式。 PDT使用可见光的肿瘤局部肿瘤（PS）的激活，并通过生成细胞毒性单线氧诱导肿瘤细胞的损害。在罗斯韦尔公园癌症研究所（Roswell Park Cancer Institute），PDT组确定了一个高度有希望的PS（HPPH），该PS（HPPH）目前正在I/II期临床试验中。为了探索头颈部鳞状细胞癌（HNSCC）中PDT和病毒疗法的潜力，我们建议研究PDT诱导的局部肿瘤损伤的影响以及在小鼠Xenograpt模型中病毒疗法治疗的血管通透性对病毒疗法治疗抗肿瘤效果的影响。我们发现，虽然仅重组溶瘤疫苗病毒（ROVV）对随时间的减少肿瘤体积有影响，但与最佳治愈性PDT方案的联合治疗可改善抗肿瘤反应和无肿瘤生存期。我们假设导致血管通透性增加的最佳PDT治疗条件将增强肿瘤组织中ROVV的摄取和复制，从而导致原发性肿瘤消融和长期控制传播疾病。在这里，我们建议单独和组合优化ROVV和PDT处理，并阐明PDT介导的HNSCC人类肿瘤中ROVV病毒疗法增强的机制。具体目的是：i）我们将分析SCC异种移植物之间的组织学结构和血管差异的程度会影响肿瘤病变中的ROVV复制； ii）使用HPPH及其碳水化合物共轭物（HPPH-GAL），我们将研究肿瘤形态，血管性以及ABCG2转运蛋白对PDT治疗功效的影响； iii）我们将探索相对于PDT的ROVV递送的动力学，以最大程度地结合两种治疗方法的好处。 PDT会导致血管泄漏和局部肿瘤损害，但是PDT后局部组织反应的程度如何影响溶瘤病毒的摄取。这两个程序具有不同的作用机理，并且将两种治疗方法结合起来可能会有额外的好处。绩效地点（S）（组织，城市，州）罗斯威尔公园癌症研究所ELM和Carlton Street Buffalo，NY 14263 公共卫生相关性：使用PDT增强溶瘤病毒疗法的功效，我们建议研究光动力疗法（PDT）诱导的局部肿瘤损伤以及血管通透性对使用人类颈部和颈部squn骨squnemous squamous cant carcinode normass n n n n n n n n n n n n n hnnnogscccccccccccccccccccccccccccccccccccccccccccccccced insopolotic疗法治疗的抗肿瘤疗法治疗抗肿瘤疗法疗效的影响。我们假设最佳的PDT治疗条件导致血管通透性增加将增强肿瘤组织中溶瘤疫苗病毒的摄取和复制，从而导致原发性肿瘤消融和长期控制传播疾病。

项目成果

CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells.

• DOI: 10.4049/jimmunol.1400201
• 发表时间: 2014-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Gil M;Komorowski MP;Seshadri M;Rokita H;McGray AJ;Opyrchal M;Odunsi KO;Kozbor D
• 通讯作者: Kozbor D