STING Activating Synthetic Nanovaccine for HPV-Induced Cancers

摘要 人乳头瘤病毒（HPV）感染是导致女性宫颈癌的首要原因 国际吧此外，HPV引起的头颈部和肛门生殖器癌也在增加， 美国的男性和女性人口。免疫疗法正在成为一种重要的 除了手术、放射治疗和化学治疗之外，癌症护理的组成部分。 检查点抑制剂和过继性细胞转移治疗，如嵌合抗原受体T 细胞疗法在黑色素瘤，非小细胞肺癌， 和肾细胞癌患者。然而，免疫相关的毒性，高成本， 不可持续记忆T细胞免疫是T细胞免疫快速采用的主要限制， 病人护理中的治疗。最近，我们建立了一种STING激活聚合物纳米疫苗， 以增强针对各种实体癌的肿瘤特异性T细胞免疫。纳米疫苗 由抗原与合成聚合物纳米颗粒PC 7A的物理混合物组成 NP，它产生了强大的细胞毒性T淋巴细胞（CTL）反应和长期记忆T 细胞免疫，全身性细胞因子释放低。PC 7A纳米疫苗产生的有效肿瘤 在黑色素瘤、结直肠癌和人类中生长抑制和长期存活增加 在小鼠中的乳头瘤病毒（HPV）-E6/E7肿瘤模型。在本应用程序中，我们将测试 假设PC 7A与STING的直接结合将导致STING从ER重新分布到 高尔基体的先天刺激，此外，抑制免疫检查点升高， STING激活将克服肿瘤对PC 7A纳米疫苗的抗性。创新实施 具体目的如下：（1）研究STING激活的生化机制， PC 7A聚合物。(2)研究疫苗耐药的机制。(3)探讨 纳米疫苗在展示人HLA-A2的转基因小鼠模型中的功效。成功 这项研究的执行将导致一种用于HPV免疫治疗的合成纳米疫苗- 诱发癌症。所提出的PC 7A纳米疫苗和检查点抑制策略可以 也可用于其他类型癌症的免疫治疗。

Abstract Human papilloma virus (HPV) infection is the primary cause of cervical cancer in women worldwide. In addition, HPV-induced head and neck and anogenital cancers are also rising in both male and female populations in the US. Immunotherapy is becoming an important component of cancer care in addition to surgery, radiation therapy and chemotherapy. Checkpoint inhibitors and adoptive cell transfer therapy such as chimeric antigen receptor T cell therapy have shown durable patient response in melanoma, non-small cell lung cancer, and renal cell cancer patients. However, immune-related toxicity, high costs, and unsustainable memory T cell immunity are major limitations for the rapid adoption of T cell therapy in patient care. Recently, we established a STING-activating polymeric nanovaccine to boost tumor-specific T cell immunity against various solid cancers. The nanovaccine consists of a physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated robust cytotoxic T lymphocyte (CTL) response and long-term memory T cell immunity with low systemic cytokines release. PC7A nanovaccine produced potent tumor growth inhibition and increased long-term survival in melanoma, colorectal cancer and human papilloma virus (HPV)-E6/E7 tumor models in mice. In this application, we will test the hypothesis that direct binding of PC7A to STING will lead to STING redistribution from ER to Golgi for innate stimulation and furthermore, inhibiting immune checkpoints elevated by STING activation will overcome tumor resistance to PC7A nanovaccine. We will carry out the following specific aims: (1) Investigate the biochemical mechanism of STING activation by PC7A polymer. (2) Investigate the mechanism of vaccine resistance. (3) Investigate nanovaccine efficacy in a transgenic mouse model displaying human HLA-A2. Successful execution of this research will lead to a synthetic nanovaccine for immunotherapy of HPV- induced cancers. The proposed PC7A nanovaccine and checkpoint inhibition strategy can also be adopted for immunotherapy of other types of cancers.