Programmable Off-the-Shelf Dendritic Cells as an Immunotherapy Discovery Platform
可编程现成树突状细胞作为免疫治疗发现平台
基本信息
- 批准号:10449196
- 负责人:
- 金额:$ 39.17万
- 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
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive ImmunotherapyAllelesAllogenicAntigen-Presenting CellsAntigensAutologousAwardBase PairingBasic ScienceBindingCell LineCell physiologyCellsClinicCommunicable DiseasesComplexConsumptionCustomCytotoxic T-LymphocytesDNADendritic Cell VaccineDendritic CellsEndogenous RetrovirusesEngineeringGenesGeneticGenomeGoalsHLA AntigensHaplotypesHarvestHumanHuman GenomeImmuneImmune systemImmunotherapyIn VitroIndustrializationInvestmentsLibrariesMalignant NeoplasmsMarshalMature T-LymphocyteMethodsModificationNational Institute of Allergy and Infectious DiseasePatientsPeptidesPersonsPopulationPositioning AttributeProceduresProliferatingReporterResearchResearch PersonnelRoleSafetySolid NeoplasmSourceStressStretchingSurfaceSystemT-Cell ActivationT-Cell ReceptorT-LymphocyteTechnologyTestingTherapeuticTimeTrainingTransgenesTumor AntigensTumor-Infiltrating LymphocytesUntranslated RNAVaccinesValidationVisionWorkWritingcancer immunotherapycareerchemotherapychimeric antigen receptorcombinatorialdirected differentiationefficacy testingengineered T cellsepigenetic silencinggenome-widehigh rewardhigh riskinduced pluripotent stem cellinduced pluripotent stem cell technologyinnovationinvestigator trainingmonocyteneoplastic cellnew technologynext generation sequencingnovel therapeuticsperipheral bloodprogramsreceptorrefractory cancersynthetic biologytechnology developmenttumor
项目摘要
Project Summary
Adoptive Cell Immunotherapy using patient harvested T cells engineered against tumor-specific targets has
ushered in a new therapeutic era. However, the lack of tumor-specific targets and T cell receptors limits the
addressable cancers. A promising approach for solid tumors uses T cell receptors (TCRs) directed against tumor-
specific antigens (TSAs) displayed on HLA receptors found on the surface of nearly every cell. Unfortunately,
HLAs are highly polymorphic genes between people. This restricts both the TCRs and TSAs to a small number
of patients. A platform that expands the number of HLA-restricted TSAs and TCRs will transform the entire
immunotherapy pipeline.
Here, I propose to address this unmet need by generating programmable Dendritic cells (DCs) – professional
antigen presenting cells that function to mature and activate naive T cells. Programmable DCs would permit the
discovery of new TCRs, validation of TSAs, and perhaps be used as "living" vaccines to marshal a patient’s own
immune system against infectious disease and cancer. Thus far, efforts to leverage the potential of DCs have
been limited principally by: (1) an inability to produce cells with HLAs matched to patients;; (2) an inability to
robustly test and validate new TSAs against TCRs;; and (3) an inability to produce "off-the-shelf" DCs at industrial
scale.
As a new innovator, my vision is to produce off-the-shelf Dendritic Cells pre-engineered to match any HLA
haplotype (even rare ones) and pre-encoded with any combination of TSAs. Using this new platform, my group
will search for and validate "universal" TSAs/TCRs that can be used broadly in TCR-Therapy for any patient.
Specifically, we will focus on peptides expressed from regions of the genome normally epigenetically silenced,
but re-activated in tumor cells (such as endogenous retroviruses). To reach this goal, we will continue
development of technology enabling the "writing" of millions of base-pairs of DNA in human induced pluripotent
stem cells (iPSCs). This technology allows direct customization of the large HLA locus of iPSCs in a single step;;
introduction of libraries of potential TSAs;; and integration of synthetic reporter constructs (which are excisable
for safety) for enhancing the in vitro directed differentiation of iPSCs to DCs. Thus, allogeneic programmed DCs
will catalyze a wide variety of immunotherapy applications and expand access of these advanced treatments for
a greater number of patients.
项目摘要
使用患者收获的 T 细胞进行过继细胞免疫治疗,针对肿瘤特异性靶点进行改造
开创了一个新的治疗时代。 然而,缺乏肿瘤特异性靶点和 T 细胞受体限制了
可解决的癌症。 治疗实体瘤的一种有前途的方法是使用针对肿瘤的 T 细胞受体 (TCR) -
几乎每个细胞表面的 HLA 受体上都有特定抗原 (TSA)。 很遗憾,
HLA 是人与人之间高度多态性的基因。 这将 TCR 和 TSA 限制为较小的数量
患者数量。 一个能够扩大 HLA 限制的 TSA 和 TCR 数量的平台将改变整个行业
免疫疗法管道。
在这里,我建议通过生成可编程树突状细胞 (DC) 来解决这一未满足的需求 – 专业
抗原呈递细胞,其功能是成熟并激活初始 T 细胞。 可编程 DC 将允许
发现新的 TCR、验证 TSA,并可能用作“活”疫苗来整理患者自己的疫苗
免疫系统对抗传染病和癌症。 迄今为止,利用发展中国家潜力的努力已取得进展
主要受到以下限制:(1) 无法产生与患者 HLA 相匹配的细胞;; (2) 无法
针对 TCR 强有力地测试和验证新的 TSA;以及 (3) 无法在工业界生产“现成的”DC
规模。
作为一名新的创新者,我的愿景是生产预设计的现成树突状细胞,以匹配任何 HLA
单倍型(甚至是罕见的)并使用 TSA 的任何组合进行预编码。 使用这个新平台,我的团队
将搜索并验证可广泛用于任何患者 TCR 治疗的“通用”TSA/TCR。
具体来说,我们将重点关注通常表观遗传沉默的基因组区域表达的肽,
但在肿瘤细胞中重新激活(例如内源性逆转录病毒)。 为了实现这一目标,我们将继续
技术的发展使得人类诱导多能性中数百万个 DNA 碱基对的“写入”成为可能
干细胞(iPSC)。 该技术允许一步直接定制 iPSC 的大型 HLA 基因座;;
引入潜在 TSA 文库;以及合成报告构建体的整合(可征税)
为了安全起见),用于增强 iPSC 与 DC 的体外定向分化。 因此,同种异体编程的 DC
将促进多种免疫治疗应用,并扩大这些先进治疗方法的可及性
更多的患者。
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)
专利数量(0)
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David Minh Truong其他文献
David Minh Truong的其他文献
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{{ truncateString('David Minh Truong', 18)}}的其他基金
Programmable Off-the-Shelf Dendritic Cells as an Off-the-Shelf Immunotherapy Discovery Platform
可编程现成树突状细胞作为现成免疫治疗发现平台
- 批准号:
10564837 - 财政年份:2021
- 资助金额:
$ 39.17万 - 项目类别:
Programmable Off-the-Shelf Dendritic Cells as an Immunotherapy Discovery Platform
可编程现成树突状细胞作为免疫治疗发现平台
- 批准号:
10684656 - 财政年份:2021
- 资助金额:
$ 39.17万 - 项目类别:
Programmable Off-the-Shelf Dendritic Cells as an Immunotherapy Discovery Platform
可编程现成树突状细胞作为免疫治疗发现平台
- 批准号:
10051095 - 财政年份:2021
- 资助金额:
$ 39.17万 - 项目类别:
Programmable Off-the-Shelf Dendritic Cells as an Immunotherapy Discovery Platform
可编程现成树突状细胞作为免疫治疗发现平台
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10770601 - 财政年份:2021
- 资助金额:
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Humanized synthetic chromosomes built in yeast for organ xenotransplantation
酵母中内置人源化合成染色体用于器官异种移植
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9305101 - 财政年份:2015
- 资助金额:
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Humanized synthetic chromosomes built in yeast for organ xenotransplantation
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