STING Activating Synthetic Nanovaccine for HPV-Induced Cancers
STING 激活合成纳米疫苗治疗 HPV 诱发的癌症
基本信息
- 批准号:10371057
- 负责人:
- 金额:$ 36.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdoptedAdoptionAdoptive Cell TransfersAnogenital cancerAntigen-Presenting CellsAntigensBacteriaBindingBinding SitesBiochemicalCAR T cell therapyCancer PatientColorectal CancerCytotoxic T-LymphocytesEpitopesFemaleGolgi ApparatusHLA-A2 AntigenHead CancerHumanHuman PapillomavirusHuman papilloma virus infectionImmuneImmune checkpoint inhibitorImmunityImmunotherapyInterferon Type ILigandsListeria monocytogenesMalignant NeoplasmsMalignant neoplasm of cervix uteriModelingMusNeck CancerNivolumabNon-Small-Cell Lung CarcinomaOperative Surgical ProceduresPathway interactionsPatient CarePatientsPeptidesPolymersPopulationPreventionPreventive vaccineProductionRadiation therapyRenal Cell CarcinomaResearchResistanceSafetySignal TransductionSolidSting InjuryT cell therapyT memory cellT-Cell ReceptorT-LymphocyteTestingTimeToxic effectTransgenic MiceTryptophan 2,3 DioxygenaseVaccinesWomanWorkcancer carecancer typecheckpoint inhibitionchemotherapycostcytokineeffective therapyengineered T cellsimmune checkpointipilimumablong term memorylung cancer cellmalemelanomamouse modelnanoparticlenanovaccinepatient responsepembrolizumabprogrammed cell death ligand 1responsespatiotemporaltherapeutic vaccinetraffickingtumortumor eradicationtumor growthvirus related cancer
项目摘要
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.
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纳米疫苗的耐药性。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。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Prolonged activation of innate immune pathways by a polyvalent STING agonist.
- DOI:10.1038/s41551-020-00675-9
- 发表时间:2021-05
- 期刊:
- 影响因子:28.1
- 作者:Li S;Luo M;Wang Z;Feng Q;Wilhelm J;Wang X;Li W;Wang J;Cholka A;Fu YX;Sumer BD;Yu H;Gao J
- 通讯作者:Gao J
Exploiting nanoscale cooperativity for precision medicine.
- DOI:10.1016/j.addr.2020.08.012
- 发表时间:2020
- 期刊:
- 影响因子:16.1
- 作者:Wilhelm J;Wang Z;Sumer BD;Gao J
- 通讯作者:Gao J
Polyvalent design in the cGAS-STING pathway.
- DOI:10.1016/j.smim.2021.101580
- 发表时间:2021-08
- 期刊:
- 影响因子:7.8
- 作者:Bennett ZT;Li S;Sumer BD;Gao J
- 通讯作者:Gao J
Antigen folding improves loading efficiency and antitumor efficacy of PC7A nanoparticle vaccine.
- DOI:10.1016/j.jconrel.2020.11.056
- 发表时间:2021-01-10
- 期刊:
- 影响因子:0
- 作者:Wilhelm J;Quiñones-Pérez M;Wang J;Wang X;Basava VS;Gao J
- 通讯作者:Gao J
Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window.
- DOI:10.1038/s41467-020-19651-7
- 发表时间:2020-11-17
- 期刊:
- 影响因子:16.6
- 作者:Wang X;Wilhelm J;Li W;Li S;Wang Z;Huang G;Wang J;Tang H;Khorsandi S;Sun Z;Evers B;Gao J
- 通讯作者:Gao J
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{{ truncateString('Jinming Gao', 18)}}的其他基金
STING Activating Synthetic Nanovaccine for HPV-Induced Cancers
STING 激活合成纳米疫苗治疗 HPV 诱发的癌症
- 批准号:
9892979 - 财政年份:2018
- 资助金额:
$ 36.89万 - 项目类别:
STING Activating Synthetic Nanovaccine for HPV-Induced Cancers
STING 激活合成纳米疫苗治疗 HPV 诱发的癌症
- 批准号:
10113555 - 财政年份:2018
- 资助金额:
$ 36.89万 - 项目类别:
STING-Activating Polymeric Nanovaccines for T Cell Therapy of Melanoma
用于黑色素瘤 T 细胞治疗的 STING 激活聚合物纳米疫苗
- 批准号:
9982225 - 财政年份:2017
- 资助金额:
$ 36.89万 - 项目类别:
STING-Activating Polymeric Nanovaccines for T Cell Therapy of Melanoma
用于黑色素瘤 T 细胞治疗的 STING 激活聚合物纳米疫苗
- 批准号:
9754799 - 财政年份:2017
- 资助金额:
$ 36.89万 - 项目类别:
STING-Activating Polymeric Nanovaccines for T Cell Therapy of Melanoma
用于黑色素瘤 T 细胞治疗的 STING 激活聚合物纳米疫苗
- 批准号:
9371064 - 财政年份:2017
- 资助金额:
$ 36.89万 - 项目类别:
STING-Activating Polymeric Nanovaccines for T Cell Therapy of Melanoma
用于黑色素瘤 T 细胞治疗的 STING 激活聚合物纳米疫苗
- 批准号:
10229423 - 财政年份:2017
- 资助金额:
$ 36.89万 - 项目类别:
Ultra-Responsive "ON/OFF" Fluorescent Nanoprobes for Cancer Molecular Imaging
用于癌症分子成像的超响应“开/关”荧光纳米探针
- 批准号:
8705515 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Ultra-Responsive "ON/OFF" Fluorescent Nanoprobes for Cancer Molecular Imaging
用于癌症分子成像的超响应“开/关”荧光纳米探针
- 批准号:
8193961 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
Ultra-Responsive "ON/OFF" Fluorescent Nanoprobes for Cancer Molecular Imaging
用于癌症分子成像的超响应“开/关”荧光纳米探针
- 批准号:
8516037 - 财政年份:2011
- 资助金额:
$ 36.89万 - 项目类别:
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