Remotely controlled listerial bactodrones for cancer immunotherapy
Remotely controlled listerial bactodrones for cancer immunotherapy
批准号:
10318673
负责人:
Jason Gigley
金额:
$15.94万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-01 至 2023-12-31
关键词:
4T1ActinsAgonistAntigen-Presenting CellsAttenuatedBacteriaBenignBloodBreast Cancer CellBreast Cancer ModelBreast Cancer cell lineCCL2 geneCD8-Positive T-LymphocytesCancer BiologyCancer ModelCause of DeathCell DeathCellsCervicalChemicalsClinical TrialsCytosolDinucleoside PhosphatesDisseminated Malignant NeoplasmEngineeringEnsureEnzymesGenesGeneticGenetic EngineeringGoalsHumanImmuneImmune checkpoint inhibitorImmunooncologyImmunotherapyIn VitroInflammatory ResponseInjectionsInnate Immune SystemInterferon Type IInterferon-betaInterferonsInterleukin-12Interleukin-2IntravenousLeadListeria monocytogenesMalignant NeoplasmsMediatingMetastatic breast cancerModalityMusMyeloid-derived suppressor cellsNatural ImmunityNeoplasm MetastasisNon-Small-Cell Lung CarcinomaNucleotidesPathway interactionsPerformancePeriodicityPlasmaPlasmidsPre-Clinical ModelPrimary NeoplasmProcessProductionProstateProtocols documentationRiskSTING agonistsSignal TransductionSiteSystemT-LymphocyteTNF geneTechnologyTestingTherapeuticTissuesToxic effectTreatment CostTumor Antigensanti-cancerbasecancer immunotherapycell motilitycheckpoint therapychemical synthesiscytokinedelivery vehicledesigndiguanylate cyclasedimerefficacy testinggenetic payloadimmunogenicimprovedin vivoinnovationintravenous injectionmalignant breast neoplasmneoplastic cellprotocol developmentrecruitresponsesynthetic biologytumortumor growthtumor microenvironmenttumor-immune system interactions
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Attenuated and avirulent strains of Listeria monocytogenes (Lm), that are delivered via intravenous injections,
accumulate and propagate in primary tumors and metastases while being quickly cleared from healthy tissues.
We intend to use these strains as remotely controlled, tumor-specific anticancer payload delivery vehicles,
bactodrones. In this project we will engineer Lm to synthesize and secrete cyclic dinucleotides (c-di-NMPs) as
potent innate immune system stimulators inside tumor microenvironments. On-site accumulation of c-di-NMPs
will induce production of type I interferon via the STING innate immunity pathway. This will improve the
capacity of Lm to induce immunogenic tumor cell death and lead to the release of tumor-associated antigens,
which will facilitate recruitment of tumor-specific CD8 T cells. The sustained tumor-localized c-di-NMP
production will keep T cells and other anticancer immune cells activated. To assess feasibility and efficacy of
delivering intratumoral c-di-NMP via genetically engineered Lm, we will pursue two aims. In aim 1, we will
engineer Lm to secrete enzymes for c-di-NMP synthesis in immune and tumor cells. In aim 2, the engineered
Lm will deliver plasmids encoding a c-di-NMP synthases, via a process known as bactofection. Both
approaches are expected to turn infected cells in the tumor microenvironment into c-di-NMP producing
factories and ensure durable STING activation. Importantly, Lm-mediated c-di-NMP delivery systems will be
made inducible with a benign chemical inducer, which will enable temporal control of STING activation and
limit toxicity associated with systemic c-di-NMP exposure. Following optimization of the Lm bactodrones in
vitro, and in breast cancer cell line, we will test efficacy of periodic bactodrone injections in a mouse metastatic
breast cancer model. We anticipate that Lm bactodrones will become efficient vehicles for tumor-localized,
temporally controlled and inexpensive delivery of genetic payloads for various antitumor activities.
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专著(0)
科研奖励(0)
会议论文
Role of Available Iron in Development of Chronic Toxoplasma gondii and Immunity
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批准号:10371561
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项目类别:
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资助金额:$17.65万
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财政年份:2021
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负责人:Jason Gigley
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依托单位:
海外基金