A novel gene therapy approach targeting STING-silenced cold tumors
一种针对 STING 沉默冷肿瘤的新型基因治疗方法
基本信息
- 批准号:10577939
- 负责人:
- 金额:$ 22.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-09 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AgonistAntibody TherapyAntigen-Presenting CellsAntitumor ResponseBiological AssayBiological Response ModifiersCD8-Positive T-LymphocytesCOVID-19 vaccineChemotactic FactorsClinicalCollaborationsDevelopmentDiagnosisEffectivenessEngineeringFaceGene SilencingGoalsGrantHumanHyperactivityImmuneImmune checkpoint inhibitorImmune systemImmunologicsImmunosuppressionImmunotherapyIn VitroInfiltrationLegal patentLettersLinkMalignant NeoplasmsMalignant neoplasm of pancreasMessenger RNAMethodsMusPD-1 blockadePD-1/PD-L1PancreasPancreatic Ductal AdenocarcinomaPatientsPeptidesProductionPublishingRNARepressionResistanceStimulator of Interferon GenesT cell infiltrationT cell responseT-Cell ActivationT-LymphocyteTestingTherapeuticTissuesToxic effectTranslatingTreatment outcomeTumor AntigensTumor ImmunityWorkadvanced pancreatic canceranti-PD1 antibodiesanti-cancerautoinflammatory diseasescancer cellcancer immunotherapycell killingcheckpoint therapychemokinecytokinecytotoxicityeffective therapyengineered T cellsgene functiongene repressiongene therapyimmune checkpoint blockadeimmune resistanceimmunogenicityimplantationimprovedin vitro testingin vivolipid nanoparticlemRNA Expressionmigrationmultidisciplinarymutantneoplastic cellnew therapeutic targetnovelnovel therapeutic interventionpancreatic cancer modelpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpreclinical studypreventrefractory cancersuccesssynergismtherapeutic nanoparticlestumortumor DNAtumor microenvironmenttumor specificitytumor-immune system interactionsultrasound
项目摘要
Project Summary
Tumor immune suppression represents a major obstacle in achieving effective cancer
immunotherapy. The goal of this exploratory project is to develop a novel mRNA-lipid
nanoparticle (mRNA-LNP)-based immunotherapy to overcome this challenge in pancreatic
cancer, one of the deadliest malignancies. Currently, few effective treatments are available for
pancreatic cancer. The majority of pancreatic cancers are also resistant to immune checkpoint
blockade. Thus, novel therapeutic strategies are needed to target this lethal cancer. Most
pancreatic cancers display a highly immunosuppressive tumor microenvironment (TME).
Tumor-infiltrating effector CD8+ T cells are critical for improved patient survival, and yet they are
either absent or sparse in the majority of pancreatic cancers, indicating an intrinsic mechanism
that impedes T cell infiltration and activation. We recently discovered that Stimulator of
Interferon Genes (STING) is silenced in pancreatic and other cancers. Because STING function
is critical for stimulating antitumor T cell responses, our finding suggests that STING silencing
contributes to the immunologically “cold” TME. We found that reactivating STING upregulates
cytokines/chemokines that are crucial for promoting intratumoral T cell infiltration. More
importantly, reactivation of STING specifically kills STING-silenced cancer cells. Because tumor
antigens released by dying cancer cells in vivo could be engulfed by antigen-presenting cells to
generate systemic antitumor response and amplify tumoricidal effect, we hypothesize that
targeted reactivation of STING in pancreatic cancer could invigorate the immune-dampened
TME and improve tumor immunogenicity. In this project, we will develop mRNA-LNP to
specifically deliver permanently active STING mutants into pancreatic cancer to bolster T cell
antitumor cytotoxicity. This approach aims to overcome the limitations of traditional STING
agonists, which lack tumor specificity and do not work in STING-silenced cancers. To define
their efficacy in stimulating antitumor immunity, the STING mRNA-LNP will be tested in vitro and
in an orthotopic syngeneic murine pancreatic cancer model, which faithfully recapitulates the
immunobiologically “cold” TME of pancreatic cancer. We will also combine STING mRNA-LNP
with PD-1 blockade to circumvent pancreatic cancer resistance to the immune checkpoint
therapy and spur synergistic antitumoral activity. These preclinical studies have the potential for
developing a novel immunotherapy to overcome immune resistance and improve treatments for
a diverse array of STING-silenced cancers that are refractory to current therapies.
项目摘要
Tumor immunosuppression represents a major obstacle in achieving effective cancer
免疫疗法。 The goal of this exploratory project is to develop a novel mRNA-lipid
nanoparticle (mRNA-LNP)-based immunotherapy to overcome this challenge in pancreatic
cancer, one of the deadliest malignancies. Currently, few effective treatments are available for
胰腺癌。 The majority of pancreatic cancers are also resistant to immuno checkpoint
封锁。 Thus, novel therapeutic strategies are needed to target this lethal cancer.最多
pancreatic cancers display a highly immunosuppressive tumor microenvironment (TME).
Tumor-infiltrating effector CD8+ T cells are critical for improved patient survival, and yet they are
either absent or sparse in the majority of pancreatic cancers, indicating an intrinsic mechanism
That impedes T cell infiltration and activation. We recently discovered that Stimulator of
Interferon Genes (STING) is silenced in pancreatic and other cancers. Because STING function
is critical for stimulating antitumor T cell responses, our finding suggests that STING silencing
contributes to the immunologically “cold” TME. We found that reactivating STING updates
cytokines/chemokines that are crucial for promoting intratumoral T cell infiltration.更多的
importantly, reactivation of STING specifically kills STING-silenced cancer cells. Because tumor
antigens released by dying cancer cells in vivo could be engulfed by antigen-presenting cells to
generate systemic antitumor response and amplify tubericidal effect, we hypothesize that
targeted reactivation of STING in pancreatic cancer could invigorate the immune-dampened
TME and improve tumor immunogenicity. In this project, we will develop mRNA-LNP to
specifically deliver permanently active STING mutants into pancreatic cancer to bolster T cell
antitumor cytotoxicity. This approach aims to overcome the limitations of traditional STING
agonists, which lack tumor specificity and do not work in STING-silenced cancers.定义
their efficiency in stimulating antitumor immunity, the STING mRNA-LNP will be tested in vitro and
in an orthotopic syngeneic murine pancreatic cancer model, which faithfully recapitulates the
immunobiologically “cold” TME of pancreatic cancer. We will also combine STING mRNA-LNP
with PD-1 blocade to circumvent pancreatic cancer resistance to the immunocheckpoint
therapy and spur synergistic antitumoral activity. These preclinical studies have the potential for
developing a novel immunotherapy to overcome immune resistance and improve treatments for
a diverse array of STING-silenced cancers that are refractory to current therapies.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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