STRATEGIES TO ENHANCE VIROTHERAPY FOR BREAST CANCER

加强乳腺癌病毒治疗的策​​略

• 批准号: 6762241
• 负责人: SHAUN XIAOLIU ZHANG
• 金额: $ 24.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6762241
• 关键词: T lymphocyte; athymic mouse; biotechnology; biotherapeutic agent; breast neoplasms; disease /disorder model; gene delivery system; gene therapy; herpes simplex virus 1; immune response; leukocyte depletion therapy; liposomes; membrane fusion; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; neoplasm /cancer transplantation; virus DNA

DESCRIPTION (provided by applicant): Breast cancer is the most common cancer of women in the United States. Despite recent improvements in conventional treatments, advanced breast cancer still has an extremely poor prognosis, resulting in more than 45,000 deaths each year in the US alone. The development of new therapeutic modalities is therefore of great importance. The long-term goal of the research outlined in this proposal is to develop an effective and safe virotherapy for metastatic breast cancer. The central hypothesis is that the antitumor activity of an oncolytic herpes simplex virus (HSV) can be significantly enhanced by incorporating a cell-membrane fusion function into the virus, which will produce syncytia formation in the tumor, thereby directly enhancing the destructive power of the virus and promoting its intratumor spread even in the presence of host's antiviral immunity. The second hypothesize is that the unique mechanism of tumor destruction in vivo by the fusogenic oncolytic HSV can induce strong antitumor immune responses, which can further facilitate tumor eradication. Specific Aim 1 seeks to determine if a doubly fusogenic oncolytic HSV, which was constructed by incorporating two independent cell-membrane fusion mechanisms into the virus, can provide effective and long-term therapy to distant organ metastases of breast cancer. The safety of this virus will also be fully assessed in this aim. Specific Aim 2 sets to explore the ability of tumor destruction by the fusogenic oncolytic HSV to induce antitumor immunity. First, the antitumor effect and the accompanying antitumor immunity induced by fusogenic and nonfusogenic oncolytic HSVs will be directly compared in a murine mammary tumor model. Then antibody depletion of immune cells (e.g., CD4+ and CD8+ T cells) will be used to determine if the tumor-specific immune response directly contributes to tumor eradication and which immune cells are responsible for the antitumor immunity. Experiments will also be conducted to dissect the mechanism of enhancement of antitumor immunity by fusogenic oncolytic HSVs. In Aim 3, the influences of pre-existing antiviral immunity on spread and antitumor effect of fusogenic and non-fusogenic HSVs in metastastic breast will be examined. Then experiments will be conducted to determine if systemic delivery of oncolytic HSV through liposome-formulation of viral DNA or through cell-carriers can evade host's antiviral immunity. The proposed studies will establish a strong preclinical rationale for using the fusogenic oncolytic HSV to treat metastatic breast cancer and will serve as the necessary foundation for a human clinical trial. Finally, if successful in breast cancer, this therapeutic strategy may be applicable to other solid tumors.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症。尽管传统治疗方法最近有所改进，但晚期乳腺癌的预后仍然极差，仅在美国每年就导致超过 45,000 人死亡。因此，开发新的治疗方法非常重要。该提案中概述的研究的长期目标是开发一种有效且安全的转移性乳腺癌病毒疗法。中心假设是，溶瘤单纯疱疹病毒（HSV）的抗肿瘤活性可以通过在病毒中融入细胞膜融合功能而显着增强，从而在肿瘤中产生合胞体形成，从而直接增强肿瘤的破坏力。即使在宿主存在抗病毒免疫力的情况下，病毒也会促进其在肿瘤内的传播。第二个假设是，融合溶瘤HSV在体内破坏肿瘤的独特机制可以诱导强烈的抗肿瘤免疫反应，从而进一步促进肿瘤的根除。具体目标1旨在确定通过将两种独立的细胞膜融合机制整合到病毒中而构建的双融合溶瘤HSV是否可以为乳腺癌远处器官转移提供有效且长期的治疗。为此，还将全面评估该病毒的安全性。具体目标 2 旨在探索融合溶瘤 HSV 破坏肿瘤以诱导抗肿瘤免疫的能力。首先，将在小鼠乳腺肿瘤模型中直接比较融合性和非融合性溶瘤HSV诱导的抗肿瘤作用和伴随的抗肿瘤免疫。然后，免疫细胞（例如 CD4+ 和 CD8+ T 细胞）的抗体耗竭将用于确定肿瘤特异性免疫反应是否直接有助于肿瘤根除以及哪些免疫细胞负责抗肿瘤免疫。还将进行实验来剖析融合溶瘤HSV增强抗肿瘤免疫的机制。在目标 3 中，将检查转移性乳腺中先前存在的抗病毒免疫对融合和非融合 HSV 的传播和抗肿瘤作用的影响。然后将进行实验以确定通过病毒DNA的脂质体制剂或通过细胞载体全身递送溶瘤HSV是否可以逃避宿主的抗病毒免疫。拟议的研究将为使用融合溶瘤 HSV 治疗转移性乳腺癌建立强有力的临床前理论基础，并将作为人体临床试验的必要基础。最后，如果在乳腺癌中取得成功，这种治疗策略可能适用于其他实体瘤。