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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，与其他实体瘤一样，限制了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。这项建议阐述了导致儿科肿瘤免疫耐药的三种机制：1)低突变负荷，2)髓系免疫抑制环境，3)MHC下调(免疫编辑)。我们已经开发了一个基于多模式病毒的疫苗平台，它利用病毒的自然能力招募免疫细胞并打破免疫耐受，以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自身抗原，使其在感染期间得到表达，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。我们的提案中描述的研究试图改进我们的基于病毒的多模式疫苗方法，以克服对最难治疗的实体肿瘤之一--恶性胶质瘤的免疫限制。我们建议验证我们的假设：通过工程病毒修饰来增强天然和过继免疫细胞活性，将通过以下目的改善治疗耐药的儿童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.