STING Activating Synthetic Nanovaccine for HPV-Induced Cancers

摘要 人乳头瘤病毒(HPV)感染是女性宫颈癌的主要原因 全世界。此外，由HPV引起的头颈部和肛门癌的发病率也在上升。 美国的男性和女性人口都是如此。免疫疗法正在成为一种重要的 除手术、放射治疗和化疗外，癌症护理的组成部分。 检查点抑制剂和过继细胞转移疗法，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，与免疫相关的毒性、高昂的成本和 不可持续的记忆性T细胞免疫是T细胞迅速被采用的主要限制 病人护理中的治疗。最近，我们建立了一种刺激性聚合物纳米疫苗。 增强肿瘤特异性T细胞免疫，对抗各种实体癌。纳米疫苗 由抗原与合成的聚合物纳米颗粒PC7A的物理混合物组成 NP，可产生强大的细胞毒性T淋巴细胞(CTL)反应和长期记忆T 全身性细胞因子释放低的细胞免疫。PC7A纳米疫苗产生有效肿瘤 黑色素瘤、结直肠癌和人类的生长抑制和长期生存增加 小鼠乳头状瘤病毒E6/E7肿瘤模型的建立。在此应用程序中，我们将测试 假设PC7A与STING的直接结合将导致STINT从内质网重新分布到 高尔基体用于先天刺激，此外，抑制免疫检查点通过 STING激活将克服肿瘤对PC7A纳米疫苗的耐药性。我们将执行 具体目的如下：(1)研究刺痛激活的生化机制。 PC7A聚合物。(2)探讨疫苗耐药机制。(三)调查 纳米疫苗在显示人人类白细胞抗原A2的转基因小鼠模型中的有效性。成功 这项研究的实施将导致一种用于HPV免疫治疗的合成纳米疫苗- 诱发癌症。建议的PC7A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.