Diversity Supplement: Hernandez-Aguirre- Cripe U54

摘要-项目3： 增强抗原和细胞因子的表达打破免疫耐受，提高抗肿瘤能力 响应 像其他实体肿瘤一样，胶质瘤限制了对变异癌细胞的免疫识别。使情况进一步复杂化的是， 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。这项建议解决了导致免疫耐药的三种机制 儿童肿瘤：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，它使用 病毒招募免疫细胞和打破免疫耐受以提高免疫活性的天然能力 肿瘤。通过在病毒基因组中编码与肿瘤相关的自身抗原，使其得以表达 在感染期间，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。这个 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 免疫抑制是最难治疗的实体瘤之一，恶性胶质瘤。我们建议测试我们的 假设：经工程改造的病毒可增强原生和后继免疫细胞活性 通过以下目的提高儿童耐药胶质瘤的持久抗肿瘤活性。 目的1：通过病毒介导的肿瘤相关性提高免疫介导的抗肿瘤反应 胎儿抗原(TAFA)的表达。假设：基于病毒的TAFA表达增强T细胞活性 肿瘤蛋白，并将在病毒复制停止后延长抗肿瘤活性。 目的2：促进抗原提呈和持久的抗肿瘤免疫反应。假设： 设计高亲和力抗原将增强其在肿瘤相关巨噬细胞中的摄取，并改善 持久的抗肿瘤反应。 目的3：通过联合细胞毒性细胞疗法和溶瘤单纯疱疹病毒来增强抗肿瘤活性 改善免疫细胞的募集和活性。假设：增强细胞毒作用的病毒 在免疫编辑的肿瘤环境中，治疗招募和活性将提高抗肿瘤效果 影响：如果成功，这个灵活的多模式病毒疫苗平台将利用和指导免疫 新一代OHSV的刺激特性与细胞免疫疗法相结合以增强 它们对低突变负荷免疫治疗耐药肿瘤的活性因此很好地符合 儿童免疫治疗药物和发展网络(PI-DDN)。

Abstract – Project 3: 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. Aim 1: To improve the immune mediated antitumor response through virus based tumor associated Fetal Antigen (TAFA) expression. Hypothesis: Viral based TAFA expression enhances T cell activity against tumor proteins and will extend anti-tumor activity after viral replication ceases. Aim 2: To promote antigen presentation and a durable anti-tumor immune response. Hypothesis: Engineering high affinity antigens will enhance their uptake in tumor associated macrophages and improve the durable anti-tumor response. Aim 3: To enhance antitumor activity by combining cytotoxic cellular therapies with oncolytic HSVs that improve immune cell recruitment and activity. Hypothesis: Viruses that enhance cytotoxic cellular therapy recruitment and activity will improve anti-tumor effect in the immunoedited tumor environment Impact: If successful, this flexible multimodal viral vaccine platform will harness and direct the immune stimulatory properties of a next generation oHSV in combination with cellular immune therapies to enhance their activity against low mutational load immunotherapy-resistant tumors and thus fits well into the aims of the Pediatric Immunotherapy Drug and Development Network (PI-DDN).