STRATEGIES TO ENHANCE VIROTHERAPY FOR BREAST CANCER

加强乳腺癌病毒治疗的策​​略

• 批准号: 7012296
• 负责人: SHAUN XIAOLIU ZHANG
• 金额: $ 24.1万
• 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/7012296
• 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）：乳腺癌是美国最常见的妇女癌。尽管传统治疗最近有所改善，但晚期乳腺癌的预后仍然非常差，仅在美国，每年就会导致45,000多人死亡。因此，新的治疗方式的发展非常重要。该提案中概述的研究的长期目标是为转移性乳腺癌开发有效且安全的病毒疗法。中心假设是，通过将细胞膜融合功能纳入病毒，可以显着增强源自源自疱疹的疱疹病毒（HSV）的抗肿瘤活性，从而在肿瘤中产生同步形成，从而直接增强病毒的破坏力，甚至增强了其内部肿瘤的破坏力，甚至可以促进其内在的宿主及其内部的抗炎。第二个假设是，融合溶瘤性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，这可以进一步促进消除肿瘤。特定目标1试图确定通过将两个独立的细胞膜融合机制纳入病毒而构建的双融合性癌性HSV是否可以为乳腺癌的远处器官转移提供有效的长期治疗。该病毒的安全性也将在此目标中得到充分评估。特定的目标2集以探索融合性癌性HSV诱导抗肿瘤免疫力的肿瘤破坏的能力。首先，将直接在鼠类乳腺肿瘤模型中直接比较融合和非溶瘤性溶性HSV引起的抗肿瘤效应和伴随的抗肿瘤免疫力。然后，将使用免疫细胞（例如CD4+和CD8+ T细胞）的抗体消耗来确定肿瘤特异性免疫反应是否直接导致消除肿瘤，哪些免疫细胞负责抗肿瘤免疫。还将进行实验，以剖析融合溶瘤性HSV增强抗肿瘤免疫力的机制。在AIM 3中，将检查预先存在的抗病毒免疫对转移乳房中融合和非舒张HSV的扩散和抗肿瘤作用的影响。然后将进行实验，以确定通过病毒DNA或通过细胞载体的脂质体成型的全身性递送肿瘤性HSV是否可以逃避宿主的抗病毒免疫。拟议的研究将建立一个强大的临床前原理，用于使用融合性溶瘤性HSV治疗转移性乳腺癌，并将作为人类临床试验的必要基础。最后，如果在乳腺癌方面取得成功，则这种治疗策略可能适用于其他实体瘤。