Admin-Core-001

管理核心-001

• 批准号: 10707767
• 负责人: TIMOTHY P CRIPE
• 金额: $ 17.21万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10707767
• 关键词: Admin; Core; 001

Enhancing antigen and cytokine expression to break immune tolerance and improve antitumor response Gliomas, like other solid tumors, restrict immune recognition of aberrant cancer cells. Further complicating this, pediatric cancers also have lower mutation rates than adult tumors making them more difficult to generate an immunotherapeutic response. This proposal addresses three mechanisms contributing to immune resistance in pediatric tumors: 1) low mutational loads, 2) myeloid immunosuppressive environment, and 3) MHC downregulation (immuno-editing). We have developed a multimodal virus based vaccine platform that uses the virus’s natural ability to recruit immune cells and break immune tolerance to improve immune activity against the tumor. By encoding tumor associated self-antigens within the viral genome so that they are expressed during infection our results show that we can convert the antiviral response into an anti-tumor response. The studies described in our proposal seek to improve our virus-based multi-modal vaccine approach to overcome immune restriction in one of the most difficult to treat solid tumors, malignant glioma. We propose testing our hypothesis that: Engineered viral modifications that enhance native and adoptive immune cell activity will improve durable anti-tumor activity in treatment resistant pediatric gliomas by the following aims.

增强抗原和细胞因子的表达以打破免疫耐受并改善抗肿瘤反应神经胶质瘤与其他实体瘤一样，限制异常癌细胞的免疫识别。更复杂的是，儿童癌症的突变率也低于成人肿瘤，这使得它们更难产生免疫治疗反应。该提案解决了导致儿科肿瘤免疫抵抗的三种机制：1）低突变负荷，2）骨髓免疫抑制环境，3）MHC 下调（免疫编辑）。我们开发了一种基于多模式病毒的疫苗平台，利用病毒招募免疫细胞和打破免疫耐受的天然能力来提高针对肿瘤的免疫活性。通过在病毒基因组内编码肿瘤相关自身抗原，以便它们在感染过程中表达，我们的结果表明，我们可以将抗病毒反应转化为抗肿瘤反应。我们提案中描述的研究旨在改进我们基于病毒的多模式疫苗方法，以克服最难治疗的实体瘤之一——恶性神经胶质瘤的免疫限制。我们建议测试我们的假设：增强天然和过继性免疫细胞活性的工程病毒修饰将通过以下目标提高治疗耐药的儿科神经胶质瘤的持久抗肿瘤活性。