Dual-pronged nano-drug delivery using plant virus-like particles
使用植物病毒样颗粒的双管齐下纳米药物输送
基本信息
- 批准号:10700990
- 负责人:
- 金额:$ 36.52万
- 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:2022-09-15 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:4T1BindingBiodistributionBiological AssayBlocking AntibodiesBloodBreast Cancer PatientCanis familiarisCellsClinicalClinical TrialsCombined Modality TherapyCompanionsCowpea Mosaic VirusesDataDevelopmentDiseaseDisseminated Malignant NeoplasmDistant MetastasisDoseDrug Delivery SystemsEngineeringEventExtracellular MatrixFemaleFlow CytometryFundingFutureGenomicsGoalsHumanImmuneImmune checkpoint inhibitorImmune systemImmunologicsImmunotherapyIn VitroInflammationInnate Immune SystemIntravenousLibrariesLifeLinkMalignant NeoplasmsMammary NeoplasmsMolecularMonitorMonoclonal AntibodiesMyelogenousNeoplasm MetastasisPatientsPatternPattern recognition receptorPeptidesPharmacologyPlant VirusesPrognosisPropertyProteinsRadiationRecurrenceResearchResourcesS100A9 geneSafetyScheduleSignal TransductionSiteSpainSpecificityT-LymphocyteTLR2 geneTestingTimeTissuesToll-like receptorsToxic effectTumor AntigensTumor ImmunityTumor MarkersVirus-like particleanti-PD-L1biophysical propertiescancer immunotherapycandidate identificationcandidate selectioncarcinogenesischeckpoint therapychemotherapyeffector T cellefficacy evaluationimmune modulating agentsimmunoregulationin situ vaccinationin vivoinsightmalignant breast neoplasmmouse modelnanodrugnanomedicinenanoparticleneoantigenspathogenpersonalized approachpharmacologicpreclinical developmentpreventprogrammed cell death ligand 1receptorresidencesafety assessmentsynergismtargeted treatmenttreatment responsetriple-negative invasive breast carcinomatumortumor growthtumor microenvironmenttumorigenesis
项目摘要
Summary
This R01 renewal application is focused on triple negative breast cancer (TNBC), which is an aggressive life-
threatening disease with poor prognosis and increased likelihood of recurrence and distant metastasis.
Advances in cancer immunotherapy have demonstrated that modulation of the patient’s immune system can
result in dramatic antitumor activity. The most promising immunotherapy approaches are those that are
personalized and take advantage of the unique neoantigens within each patient’s tumor. Toward this goal, we
developed a plant virus nanoparticle immunotherapy approach that activates innate immune cells within
the tumor microenvironment (TME) to launch adaptive, systemic, and durable antitumor immunity.
Specifically, intratumorally injected cowpea mosaic virus (CPMV) demonstrates potent efficacy in multiple mouse
models, incl. TNBC. Trials in companion dogs with breast cancer also demonstrate potent antitumor efficacy.
During the previous funding cycle, we gained insights into the mechanism of action and demonstrated that
CPMV is recognized by pathogen-associated molecular pattern (PAMP) receptors that detect danger signals
and activate the innate immune system; specifically, CPMV is recognized by Toll-like receptors (TLR2, 4 and 7).
Further, we developed and tested combination and dual-pronged treatment approaches: we demonstrated
efficacy of CPMV as solo-treatment as well as in combination with radiation, chemotherapy, immunomodulatory
drugs, and checkpoint inhibitors, amongst others. This proposal builds on this strong portfolio of data. Our first
goal is to focus on dual-pronged CPMV that combines its immunomodulatory and antitumor immunity properties
with checkpoint therapy (Aim 1). Checkpoint blocking antibodies are effective at removing inhibitory signals but
as monotherapy have variable and limited efficacy. In situ vaccination with CPMV increases tumor antigen
specific effector T cells and our preliminary data indicate that CPMV treatment synergizes with immune
checkpoint therapy. Next, we seek to develop targeted approaches that effectively concentrate systemically
administered CPMV in tumors and provide further therapy options to treat metastatic disease (Aim 2). S100A9-
targeted CPMV will be studied: expression of S100A9 (also known as myeloid-related protein 14 [MRP-14]), is
linked to inflammation and carcinogenesis. Higher S100A9 expression in breast cancer correlates with a worse
prognosis. S100A9 expression is an early event in tumorigenesis, enhancing tumor aggressiveness and
metastasis. In the TME, S100A9 is secreted to the extracellular matrix, making it a highly suitable target for
nanomedicine. Recognizing the potential of S100A9 as a pharmacologic target, we developed S100A9-targeted
CPMV that efficiently concentrates at sites of metastasis enabling potent efficacy preventing outgrowth of
metastases. Here we set out to detail the mechanisms of action and understand the pharmacology of S100A9-
targeted CPMV. Finally, the preclinical development will be substantially extended with veterinary clinical trials
in companion dogs with mammary tumors (Aim 3).
总结
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cowpea Mosaic Virus (CPMV)-Based Cancer Testis Antigen NY-ESO-1 Vaccine Elicits an Antigen-Specific Cytotoxic T Cell Response.
- DOI:10.1021/acsabm.0c00259
- 发表时间:2020-07-20
- 期刊:
- 影响因子:4.7
- 作者:Patel BK;Wang C;Lorens B;Levine AD;Steinmetz NF;Shukla S
- 通讯作者:Shukla S
Development of a Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine.
- DOI:10.3390/cancers13122909
- 发表时间:2021-06-10
- 期刊:
- 影响因子:5.2
- 作者:Hu H;Steinmetz NF
- 通讯作者:Steinmetz NF
Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.
- DOI:10.1073/pnas.2221859120
- 发表时间:2023-10-24
- 期刊:
- 影响因子:11.1
- 作者:Chung, Young Hun;Ortega-Rivera, Oscar A.;Volckaert, Britney A.;Jung, Eunkyeong;Zhao, Zhongchao;Steinmetz, Nicole F.
- 通讯作者:Steinmetz, Nicole F.
Doxorubicin-Loaded Physalis Mottle Virus Particles Function as a pH-Responsive Prodrug Enabling Cancer Therapy.
- DOI:10.1002/biot.202000077
- 发表时间:2020-12
- 期刊:
- 影响因子:4.7
- 作者:Hu H;Steinmetz NF
- 通讯作者:Steinmetz NF
Bluetongue Virus Particles as Nanoreactors for Enzyme Delivery and Cancer Therapy.
- DOI:10.1021/acs.molpharmaceut.0c01053
- 发表时间:2021-03-01
- 期刊:
- 影响因子:4.9
- 作者:Thuenemann EC;Le DHT;Lomonossoff GP;Steinmetz NF
- 通讯作者:Steinmetz NF
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{{ truncateString('Nicole Franziska Steinmetz', 18)}}的其他基金
Dual-pronged nano-drug delivery using plant virus-like particles.
使用植物病毒样颗粒进行双管齐下的纳米药物输送。
- 批准号:
9982275 - 财政年份:2018
- 资助金额:
$ 36.52万 - 项目类别:
Dual-pronged nano-drug delivery using plant virus-like particles.
使用植物病毒样颗粒进行双管齐下的纳米药物输送。
- 批准号:
10224677 - 财政年份:2018
- 资助金额:
$ 36.52万 - 项目类别:
Dual-pronged nano-drug delivery using plant virus-like particles
使用植物病毒样颗粒的双管齐下纳米药物输送
- 批准号:
9372245 - 财政年份:2017
- 资助金额:
$ 36.52万 - 项目类别:
A theranostic approach for risk stratification and intervention of deep vein thrombosis.
深静脉血栓形成风险分层和干预的治疗诊断方法。
- 批准号:
9767271 - 财政年份:2017
- 资助金额:
$ 36.52万 - 项目类别:
Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging
通过分子磁共振成像诊断和纵向监测转移性前列腺癌
- 批准号:
9208751 - 财政年份:2016
- 资助金额:
$ 36.52万 - 项目类别:
Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging.
通过分子磁共振成像诊断和纵向监测转移性前列腺癌。
- 批准号:
9755062 - 财政年份:2016
- 资助金额:
$ 36.52万 - 项目类别:
Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging.
通过分子磁共振成像诊断和纵向监测转移性前列腺癌。
- 批准号:
9629935 - 财政年份:2016
- 资助金额:
$ 36.52万 - 项目类别:
Engineering 'Grapevine Virus A' filaments for nanomedical applications
工程“葡萄病毒 A”细丝用于纳米医学应用
- 批准号:
9144385 - 财政年份:2015
- 资助金额:
$ 36.52万 - 项目类别:
Detection of lethal prostate cancer with macromolecule-based, EGFL-7 targeted MR imaging approach
使用基于大分子的 EGFL-7 靶向 MR 成像方法检测致命性前列腺癌
- 批准号:
8954282 - 财政年份:2015
- 资助金额:
$ 36.52万 - 项目类别:
Detection of lethal prostate cancer with macromolecule-based, EGFL-7 targeted MR imaging approach
使用基于大分子的 EGFL-7 靶向 MR 成像方法检测致命性前列腺癌
- 批准号:
9094573 - 财政年份:2015
- 资助金额:
$ 36.52万 - 项目类别:
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