Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy
使用纳米平台进行胰腺癌免疫治疗
基本信息
- 批准号:10654816
- 负责人:
- 金额:$ 51.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdoptive TransferAgonistAntibodiesAntigen-Presenting CellsBlocking AntibodiesC-terminalCXCR4 geneCell Death InductionCellsCholesterolCombination immunotherapyCustomCytotoxic T-LymphocytesDataDendritic CellsDesmoplasticDevelopmentDinucleoside PhosphatesDrug CombinationsDrug Delivery SystemsDuct (organ) structureEncapsulatedEnvironmentExclusionFailureGene DeliveryGenerationsGenetic EngineeringGenetic TranscriptionGlycogen Synthase Kinase 3GlycolatesGoalsImmuneImmune checkpoint inhibitorImmune responseImmuno-ChemotherapyImmunologicsImmunosuppressionImmunotherapyInnate Immune SystemIntegrin alphaVbeta3IntegrinsInterventionLipid BilayersLipidsLiverMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMemoryMetabolic PathwayMetastatic AdenocarcinomaMetastatic Neoplasm to the LiverMyeloid CellsMyeloid-derived suppressor cellsNeoplasm MetastasisNeuropilin-1OrganOutcome StudyPD-1 pathwayPD-1/PD-L1PDL1 pathwayPancreatic Ductal AdenocarcinomaPathway interactionsPatientsPenetrationPeptidesPeriodicityPharmaceutical PreparationsPharmacologic SubstancePrimary NeoplasmProdrugsResearchResistanceRoleScienceSeriesSilicon DioxideSiteSolidStimulator of Interferon GenesStimulusStromal Cell-Derived Factor 1T cell responseT memory cellT-LymphocyteTechniquesTestingTherapeuticTimeTryptophan 2,3 DioxygenaseTumor AntigensTumor-associated macrophagesVaccinationalternative treatmentcancer cellcancer immunotherapycancer sitecheckpoint receptorschemotherapeutic agentchemotherapydesignexperimental studyimmune checkpointimmunogenic cell deathimmunogenicityimmunological statusimprovedinhibitorinnovationirinotecanmetastasis preventionmigrationmortalitynanonanocarriernanoparticlenanoparticle deliverynanopolymerneoantigensnovel strategiesoverexpressionoxaliplatinpancreatic ductal adenocarcinoma modelpreventprogrammed cell death protein 1programsreceptorrecruitresponseside effectsmall molecule inhibitorsuccesssynergismtargeted deliverytranscytosistreatment strategytumortumor microenvironmentuptake
项目摘要
The use of nano-enabled chemotherapy to trigger an immune response to pancreatic ductal adenocarcinoma
(PDAC) introduces a novel approach for overcoming robust barriers to immunotherapy, including poor
immunogenicity, low neoantigen burden, stromal interference (“T-cell exclusion”), overexpression of
indoleamine 2,3-dioxygenase (IDO-1), and the immune privileged environment of the liver favoring metastatic
spread. Our preliminary data show that lipid-bilayer coated mesoporous silica nanoparticles (silicasomes)
provide an effective platform for inducing immunogenic cell death (ICD) by delivering prescreened
chemotherapeutic agents to the PDAC site. ICD promotes the presentation of endogenous tumor antigens
cells, raising the hypothesis that ICD offers a promising endogenous vaccination approach to generate a “hot”
tumor microenvironment (TME) that can be propagated by co-delivery of drugs interfering in regionally
overexpressed immunosuppressive pathways. These pathways can be targeted by inhibitors of IDO-1, CXCR4
(T-cell exclusion) and glycogen synthase kinase 3 (which controls PD-1 expression). We also propose that
metastatic spread can be reduced by ICD-induced memory T-cells and delivery of “stimulator of interferon
genes” (STING) agonists to tolerogenic antigen presenting cells in the liver. The long-term goal of our
interdisciplinary efforts is to develop a chemo-immunotherapy platform for delivery of ICD stimuli by the
silicasome contemporaneous with inhibitors of immune checkpoint and T-cell exclusion pathways (CXCR4).
The objectives include the use of innovative drug loading and cholesterol-conjugated prodrugs to synthesize
silicasomes that can be used to obtain the best synergy between ICD stimuli and inhibitors of
immunosuppressive pathways in orthotopic and genetic engineered PDAC models. This requires research
discovery into the mechanistic basis of synergy between ICD and regional immune escape pathways. We will
use an integrin-targeting, tumor-penetrating iRGD peptide to enhance drug delivery by a transcytosis pathway.
We will also construct polymeric nanocarriers to deliver STING agonists for preventing metastatic spread to the
liver. The rationale is that the use of an ICD approach to generate a “hot” tumor environment will facilitate
combination immunotherapy with improvement of PDAC mortality. We plan to test our hypothesis by pursuing
the following specific aims: Aim 1: To develop a nano-enabled chemo-immunotherapy platform for PDAC that
utilizes an endogenous (ICD-mediated) treatment approach plus interference in regionally overexpressed
immune checkpoint pathways to generate a “hot” tumor environment. Aim 2: To enhance the immunotherapy
impact of the ICD platform by using integrin-targeting, tumor-penetrating iRGD peptides and developing a
silicasome that interferes in T-cell exclusion in the stroma through the delivery of CXCR4 inhibitors. Aim #3: To
reprogram the immune suppressive effects of liver APC by STING nanoparticles that promote eradication of
PDAC metastases by the memory T-cells generated by ICD-inducing silicasomes.
纳米化疗在胰腺导管腺癌免疫治疗中的应用
(PDAC)推出了一种新的方法来克服免疫治疗的强大障碍,包括穷人
免疫原性、低新抗原负荷、基质干扰(“T细胞排斥”)、高表达
吲哚胺2,3-双加氧酶(IDO-1)与肝脏有利于转移的免疫特权环境
散开。我们的初步数据显示,脂质双层包覆的介孔二氧化硅纳米颗粒(硅酶体)
为诱导免疫原性细胞死亡(ICD)提供有效的平台
化疗药物进入PDAC部位。ICD促进内源性肿瘤抗原的呈递
细胞,提出了这样一种假设,即ICD提供了一种很有前途的内源性疫苗接种方法来产生一种“热”。
肿瘤微环境(TME)可通过区域干扰药物共给药而传播
过度表达的免疫抑制途径。这些通路可以被IDO-1、CXCR4的抑制剂靶向
(T细胞除外)和糖原合成酶激酶3(控制PD-1表达)。我们还建议
ICD诱导的记忆T细胞和“干扰素刺激物”可减少转移扩散
基因“(刺痛)激动剂对肝脏中的耐受性抗原提呈细胞。我们的长期目标是
跨学科的努力是开发一个化学免疫治疗平台,通过
硅酶体与免疫检查点和T细胞排斥途径的抑制物(CXCR4)同时存在。
目标包括使用创新的载药和胆固醇结合的前药来合成
可用于在ICD刺激物和血管紧张素转换酶抑制剂之间获得最佳协同作用的硅酶体
原位和基因工程PDAC模型中的免疫抑制途径。这需要研究
发现ICD和区域免疫逃逸途径协同作用的机制基础。我们会
使用整合素靶向、肿瘤穿透的IRGD多肽通过跨细胞途径增强药物传递。
我们还将构建聚合物纳米载体来运送刺痛激动剂,以防止转移到
肝脏。其基本原理是,使用ICD方法来产生“热”的肿瘤环境将促进
免疫治疗与提高PDAC死亡率相结合。我们计划通过以下方式来检验我们的假设
具体目标如下:目标1:开发一种用于PDAC的纳米启用的化疗免疫治疗平台
利用内源性(ICD介导的)治疗方法加上对区域性过度表达的干预
免疫检查点途径产生一个“热”的肿瘤环境。目的2:加强免疫治疗
使用整合素靶向、肿瘤穿透性IRGD多肽和开发一种
通过递送CXCR4抑制剂干扰基质中T细胞排斥的硅酶体。目标3:达到
通过刺激纳米粒促进肝APC的免疫抑制作用的重新编程
ICD诱导的硅酶体产生的记忆T细胞的PDAC转移。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multifunctional Lipid Bilayer Nanocarriers for Cancer Immunotherapy in Heterogeneous Tumor Microenvironments, Combining Immunogenic Cell Death Stimuli with Immune Modulatory Drugs.
- DOI:10.1021/acsnano.2c01252
- 发表时间:2022-04-26
- 期刊:
- 影响因子:17.1
- 作者:Nel, Andre E.;Mei, Kuo-Ching;Liao, Yu-Pei;Liu, Xiangsheng
- 通讯作者:Liu, Xiangsheng
Transformational Impact of Nanomedicine: Reconciling Outcome with Promise.
- DOI:10.1021/acs.nanolett.0c02738
- 发表时间:2020-08-12
- 期刊:
- 影响因子:10.8
- 作者:Nel AE MD/DSc
- 通讯作者:Nel AE MD/DSc
Use of Stromal Intervention and Exogenous Neoantigen Vaccination to Boost Pancreatic Cancer Chemo-Immunotherapy by Nanocarriers.
- DOI:10.3390/bioengineering10101205
- 发表时间:2023-10-16
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Andre Elias Nel其他文献
Andre Elias Nel的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Andre Elias Nel', 18)}}的其他基金
Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy
使用纳米平台进行胰腺癌免疫治疗
- 批准号:
10187533 - 财政年份:2020
- 资助金额:
$ 51.28万 - 项目类别:
Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy
使用纳米平台进行胰腺癌免疫治疗
- 批准号:
10058189 - 财政年份:2020
- 资助金额:
$ 51.28万 - 项目类别:
Use of a Nano-Enabled Platform for Pancreatic Cancer Immunotherapy
使用纳米平台进行胰腺癌免疫治疗
- 批准号:
10417161 - 财政年份:2020
- 资助金额:
$ 51.28万 - 项目类别:
Toxicological Profiling of Engineered Nanomaterials (ENMs) in the MPS (RES)
MPS (RES) 中工程纳米材料 (ENM) 的毒理学分析
- 批准号:
9186735 - 财政年份:2016
- 资助金额:
$ 51.28万 - 项目类别:
Toxicological Profiling of Engineered Nanomaterials (ENMs) in the MPS (RES)
MPS (RES) 中工程纳米材料 (ENM) 的毒理学分析
- 批准号:
9341321 - 财政年份:2016
- 资助金额:
$ 51.28万 - 项目类别:
Toxicological Profiling of Engineered Nanomaterials (ENMs) in the MPS (RES)
MPS (RES) 中工程纳米材料 (ENM) 的毒理学分析
- 批准号:
9769728 - 财政年份:2016
- 资助金额:
$ 51.28万 - 项目类别:
Nanovalve Platform: Targeted, Controlled, Release of Anticancer Drugs
Nanovalve平台:靶向、可控、释放抗癌药物
- 批准号:
8206804 - 财政年份:2010
- 资助金额:
$ 51.28万 - 项目类别:
Center for Nanobiology and Predictive Toxicology
纳米生物学和预测毒理学中心
- 批准号:
8464703 - 财政年份:2010
- 资助金额:
$ 51.28万 - 项目类别:
Center for Nanobiology and Predictive Toxicology
纳米生物学和预测毒理学中心
- 批准号:
8393965 - 财政年份:2010
- 资助金额:
$ 51.28万 - 项目类别:
相似海外基金
Time to ATTAC: Adoptive Transfer of T cells Against gp100+ Cells to treat LAM
ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
- 批准号:
10682121 - 财政年份:2023
- 资助金额:
$ 51.28万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10576370 - 财政年份:2022
- 资助金额:
$ 51.28万 - 项目类别:
Phase I clinical trial of adoptive transfer of autologous folate receptor-alpha redirected CAR T cells for ovarian cancer
自体叶酸受体-α重定向CAR T细胞过继转移治疗卵巢癌的I期临床试验
- 批准号:
10387023 - 财政年份:2022
- 资助金额:
$ 51.28万 - 项目类别:
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10248409 - 财政年份:2019
- 资助金额:
$ 51.28万 - 项目类别:
A phase I clinical study of adoptive transfer of regulatory T cells (Tregs) and low-dose interleukin-2 (IL-2) for the treatment of chronic graft-versus-host disease (GVHD): gene-marking to inform rational combination therapy
调节性 T 细胞 (Treg) 和低剂量白细胞介素 2 (IL-2) 过继转移治疗慢性移植物抗宿主病 (GVHD) 的 I 期临床研究:基因标记为合理的联合治疗提供信息
- 批准号:
nhmrc : GNT1163111 - 财政年份:2019
- 资助金额:
$ 51.28万 - 项目类别:
Project Grants
Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer
确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制
- 批准号:
10462684 - 财政年份:2019
- 资助金额:
$ 51.28万 - 项目类别:
Gene edited lymphoid progenitors for adoptive transfer as a treatment of primary immunodeficiency
基因编辑的淋巴祖细胞用于过继转移作为原发性免疫缺陷的治疗
- 批准号:
398018062 - 财政年份:2018
- 资助金额:
$ 51.28万 - 项目类别:
Research Grants
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9308643 - 财政年份:2017
- 资助金额:
$ 51.28万 - 项目类别:
Overcoming immune suppression in cancer by targeting PSGL-1 in T cells used for adoptive transfer
通过靶向用于过继转移的 T 细胞中的 PSGL-1 克服癌症中的免疫抑制
- 批准号:
9447149 - 财政年份:2017
- 资助金额:
$ 51.28万 - 项目类别:
Targeting Cancer miRNAs by Adoptive Transfer of Programmed B Lymphocytes
通过程序化 B 淋巴细胞的过继转移靶向癌症 miRNA
- 批准号:
8893915 - 财政年份:2014
- 资助金额:
$ 51.28万 - 项目类别: