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）：通过PDT增强溶瘤病毒疗法的功效使用溶瘤病毒的临床前和临床研究显示出治疗实体瘤的前景。然而，溶瘤病毒载体向肿瘤的全身递送受到载体无法有效进入靶位点的限制。我们建议探索溶瘤病毒疗法与光动力疗法 (PDT) 联合使用治疗头颈部肿瘤的潜力，其中 PDT 是一种极好的治疗方式。 PDT 利用可见光激活肿瘤定位光敏剂 (PS)，并通过产生细胞毒性单线态氧诱导对肿瘤细胞的损伤。在罗斯威尔帕克癌症研究所，PDT 小组已经确定了一种非常有前途的 PS (HPPH)，目前正在进行 I/II 期临床试验。为了探索PDT和病毒疗法联合治疗头颈鳞状细胞癌（HNSCC）的潜力，我们建议在异种移植模型中研究PDT引起的局部肿瘤损伤和血管通透性变化对病毒疗法抗肿瘤疗效的影响。老鼠。我们发现，虽然单独使用重组溶瘤痘苗病毒 (rOVV) 随着时间的推移可以减少肿瘤体积，但与最佳疗效的 PDT 方案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，从而导致原发肿瘤消融和播散性疾病的长期控制。在这里，我们建议单独和联合优化 rOVV 和 PDT 治疗，并阐明 PDT 介导的 rOVV 病毒疗法在异种移植 HNSCC 人类肿瘤中增强的机制。具体目标是： 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影响肿瘤病灶中 rOVV 复制的程度； ii) 使用HPPH及其碳水化合物缀合物（HPPH-Gal），我们将研究肿瘤形态、血管分布以及ABCG2转运蛋白的存在与否对PDT治疗效果的影响； iii) 我们将探索 rOVV 递送相对于 PDT 的动力学，以最大限度地发挥两种治疗方法相结合的益处。 PDT 会导致血管渗漏和局部肿瘤损伤，但 PDT 后局部组织反应的程度如何影响溶瘤病毒的摄取尚不清楚。这两种治疗方法具有不同的作用机制，将两种治疗方法结合起来可能会带来额外的好处。表演地点（组织、城市、州） Roswell Park Cancer Institute Elm & Carlton Streets Buffalo, NY 14263 公共健康相关性：通过PDT增强溶瘤病毒疗法的疗效我们建议研究光动力疗法（PDT）引起的局部肿瘤损伤和血管通透性变化对使用人头颈部鳞状细胞异种移植物的溶瘤病毒疗法的抗肿瘤功效的影响免疫缺陷小鼠模型中的癌症（HNSCC）。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溶瘤痘苗病毒的摄取和复制，从而导致原发肿瘤消融和播散性疾病的长期控制。

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