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胶质瘤与其他实体肿瘤一样，限制了对异常癌细胞的免疫识别。更复杂的是，儿童癌症的突变率也比成人肿瘤低，这使得它们更难以产生免疫治疗反应。该提案提出了儿童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，以及3)MHC下调（免疫编辑）。我们已经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破坏免疫耐受的自然能力来提高对肿瘤的免疫活性。通过在病毒基因组中编码肿瘤相关的自身抗原，使它们在感染期间表达，我们的研究结果表明，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态疫苗方法，以克服最难治疗的实体肿瘤之一恶性胶质瘤的免疫限制。我们提出验证我们的假设：通过以下目的，增强天然免疫细胞和过继免疫细胞活性的工程病毒修饰将提高耐药小儿胶质瘤的持久抗肿瘤活性。

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.