Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy
项目2:针对肺癌免疫治疗的新抗原
基本信息
- 批准号:10700908
- 负责人:
- 金额:$ 34.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdoptive TransferAmericanAntigen PresentationAntigensAutoantigensAutologousAvidityBindingBioinformaticsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCancer VaccinesCellsClinical DataCodeCyclic GMPDataDendritic CellsDiseaseDisease ProgressionEngineeringFailureFred Hutchinson Cancer Research CenterFunctional disorderFutureGenesGranulocyte-Macrophage Colony-Stimulating FactorHeterogeneityHistocompatibility Antigens Class IIHumanImmune checkpoint inhibitorImmune responseImmunityImmunologic MonitoringImmunosuppressionImmunotherapyInduced MutationInfusion proceduresInterleukin-12KRAS2 geneLungLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMediatingMembraneMethodsModalityModelingMusMutateMutationNon-Small-Cell Lung CarcinomaPatientsPeptidesPhase I Clinical TrialsPhysiologic pulsePre-Clinical ModelProductionProteinsRNASafetySignal TransductionSiteT cell responseT-Cell ActivationT-LymphocyteTP53 geneTherapeuticTransgenesTranslatingTumor ImmunityTumor PromotionVaccinatedVaccinationVaccine TherapyVaccinesWASP proteinantigen-specific T cellsantitumor effectcGMP productioncancer immunotherapycentral tolerancecheckpoint inhibitioncheckpoint therapyclinical applicationclinical translationcohortdesignengineered T cellsexomeexome sequencinggenetic approachimmune functionimmunogenicityimprovedinhibiting antibodyinnovationlymph nodesmelanomamortalitymouse modelneoantigen vaccinationneoantigen vaccineneoantigensneoplastic cellnovelnovel strategiesnovel therapeuticspatient subsetspersonalized approachpersonalized medicineprediction algorithmresponsesubcutaneoustherapeutic vaccinetranscriptome sequencingtumortumor microenvironmenttumor-immune system interactionsvaccine platformvector
项目摘要
Project Summary/Abstract – Project 2
Immunotherapy with immune checkpoint inhibitors (ICI) is revolutionizing the treatment of many cancers,
including non-small cell lung cancer (NSCLC) where a small subset of patients with metastatic disease have
significant responses. The antitumor activity of ICI is thought in part to be mediated by CD4+ and CD8+ T cells
that recognize neoantigens, which are peptides derived from mutations in expressed genes in tumor cells and
presented by class I or II MHC molecules. Thus, the failure of most patients to respond to ICI may result from
an insufficient pre-existing tumor-specific T cell response, irreversible dysfunction of previously activated T
cells, or local immunosuppressive mechanisms. A therapeutic vaccine capable of boosting or inducing de novo
functional T cell responses to neoantigens could be beneficial alone, or in combination with ICI or other
modalities that overcome immunosuppression in the tumor microenvironment. Putative neoantigens are
prevalent in NSCLC due to the high mutation burden, and may be superior to self-antigens as vaccine targets
because the T cell repertoire capable of responding is not affected by central tolerance mechanisms.
Moreover, multiple neoantigens can theoretically be targeted by a vaccine, which could overcome
heterogeneity in antigen and MHC expression on tumors, and in the quality of a single neoantigen. Multiple
candidate neoantigens can be identified using whole exome sequencing of tumors to detect coding mutations,
and algorithms that predict peptides likely to bind to MHC molecules. Initial clinical applications of therapeutic
neoantigen vaccines in melanoma have recently provided proof-of-principle, and revealed the potential of this
personalized approach to cancer immunotherapy.
We have developed a novel approach to neoantigen vaccination that utilizes the systemic administration of
autologous T cells engineered to express cancer-specific mutations (Tvax). This strategy was suggested by
clinical data from our lab showing that adoptive transfer of human T cells expressing transgenes encoding
foreign proteins induced potent CD8+ and CD4+ T cell responses specific for the transgene product that were
boosted by subsequent infusions, even in patients with severely compromised immunity. T cells provide a
versatile platform for personalized medicines, including cell based vaccines because they can be easily
genetically modified and expanded in cGMP conditions, safely administered systemically, and traffic efficiently
to lymph node sites to deliver antigens where immune responses are initiated. This project will translate this
unique approach for vaccination to neoantigens in preclinical models and patients with NSCLC.
项目概要/摘要-项目2
免疫检查点抑制剂(ICI)的免疫疗法正在彻底改变许多癌症的治疗方法,
包括非小细胞肺癌(NSCLC),其中一小部分患有转移性疾病的患者
重要的回应。ICI的抗肿瘤活性被认为部分由CD 4+和CD 8 + T细胞介导
其识别新抗原,所述新抗原是源自肿瘤细胞中表达基因的突变的肽,
由I类或II类MHC分子呈递。因此,大多数患者对ICI的反应失败可能是由于
预先存在的肿瘤特异性T细胞应答不足,先前活化的T细胞不可逆功能障碍,
细胞或局部免疫抑制机制。一种能够加强或诱导新生的治疗性疫苗,
对新抗原的功能性T细胞应答可以单独或与ICI或其他免疫抑制剂组合是有益的。
克服肿瘤微环境中的免疫抑制的模式。推定的新抗原是
由于高突变负荷,在NSCLC中普遍存在,并且作为疫苗靶点可能上级自身抗原
因为能够应答的T细胞库不受中枢耐受机制的影响。
此外,理论上,疫苗可以靶向多种新抗原,这可以克服
肿瘤上抗原和MHC表达的异质性,以及单一新抗原的质量。多
可以使用肿瘤的全外显子组测序来检测编码突变来鉴定候选新抗原,
以及预测可能与MHC分子结合的肽的算法。治疗的初步临床应用
黑色素瘤中的新抗原疫苗最近提供了原理证明,并揭示了这一点的潜力。
癌症免疫治疗的个性化方法。
我们已经开发了一种新抗原疫苗接种的新方法,其利用全身施用
工程化以表达癌症特异性突变的自体T细胞(Tvax)。这一战略是由
我们实验室的临床数据显示,表达转基因的人T细胞的过继转移,
外源蛋白诱导了对转基因产物特异的有效的CD 8+和CD 4 + T细胞应答,
即使在免疫力严重受损的患者中,也可以通过随后的输注来增强。T细胞提供了
个性化药物的多功能平台,包括基于细胞的疫苗,因为它们可以很容易地
在cGMP条件下进行基因修饰和扩增,安全地全身给药,并有效地运输
到淋巴结部位以递送引发免疫应答的抗原。这个项目将把这个
在临床前模型和NSCLC患者中接种新抗原的独特方法。
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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STANLEY R. RIDDELL其他文献
STANLEY R. RIDDELL的其他文献
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{{ truncateString('STANLEY R. RIDDELL', 18)}}的其他基金
Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy
项目2:针对肺癌免疫治疗的新抗原
- 批准号:
10601293 - 财政年份:2019
- 资助金额:
$ 34.66万 - 项目类别:
Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy
项目2:针对肺癌免疫治疗的新抗原
- 批准号:
10174871 - 财政年份:2019
- 资助金额:
$ 34.66万 - 项目类别:
Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy
项目2:针对肺癌免疫治疗的新抗原
- 批准号:
10436174 - 财政年份:2019
- 资助金额:
$ 34.66万 - 项目类别:
Targeting Alloreactivity for Leukemia Eradication
针对白血病根除的同种异体反应性
- 批准号:
8277822 - 财政年份:2011
- 资助金额:
$ 34.66万 - 项目类别:
STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES
增强 T 细胞克隆过继转移的策略
- 批准号:
8357607 - 财政年份:2011
- 资助金额:
$ 34.66万 - 项目类别:
STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES
增强 T 细胞克隆过继转移的策略
- 批准号:
8172773 - 财政年份:2010
- 资助金额:
$ 34.66万 - 项目类别:
EVALUATING THE ENGINEERING OF CYTOMEGALOVIRUS-SPECIFIC CD8+ T CELL CLONES
评估巨细胞病毒特异性 CD8 T 细胞克隆的工程设计
- 批准号:
8172786 - 财政年份:2010
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Targeted immunotherapy of breast cancer with central memory T cells
中央记忆T细胞对乳腺癌的靶向免疫治疗
- 批准号:
8181485 - 财政年份:2010
- 资助金额:
$ 34.66万 - 项目类别:
STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES
增强 T 细胞克隆过继转移的策略
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7958859 - 财政年份:2009
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$ 34.66万 - 项目类别:
ANALYSIS OF A NOVEL SUBSET OF HUMAN CD8+ MEMORY CELLS WITH STEM CELL QUALITIES
具有干细胞特性的新型人类 CD8 记忆细胞亚群的分析
- 批准号:
7832350 - 财政年份:2009
- 资助金额:
$ 34.66万 - 项目类别:
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