CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy
CCL3 作为一种增强脑肿瘤治疗的发育疗法
基本信息
- 批准号:9216208
- 负责人:
- 金额:$ 34.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAffectAntigensBilateralBrainBrain NeoplasmsCCR1 geneCCR5 geneCD8-Positive T-LymphocytesCancer EtiologyCellsCervicalCessation of lifeClinical TrialsCytotoxic T-LymphocytesDataDendritic Cell VaccineDendritic CellsDevelopmental Therapeutics ProgramDiphtheria ToxoidDoseGlioblastomaGliomaGoalsHumanImmuneImmunityImmunotherapyIndividualInflammationInflammatoryInjectableInterferon Type IIIntracranial NeoplasmsLaboratoriesLigandsMalignant - descriptorMalignant neoplasm of brainMediator of activation proteinMemoryMethodsModelingMusNatureNewly DiagnosedNormal tissue morphologyPatientsPharmaceutical PreparationsPhasePrimary Brain NeoplasmsProductionProgression-Free SurvivalsPublicationsPublishingRenal carcinomaRoleSignal TransductionSiteSmall Inducible Cytokine A3SourceT cell responseT-LymphocyteTNF geneTetanusToxic effectTumor AntigensTumor ImmunityVaccinationVaccinesWorkcell motilitychemokinechildhood cancer mortalitycytokinegamma-Chemokinesimmune functionimprovedindividual patientinnovationlymph nodesmelanomamigrationmouse modelnovelpre-clinicalpreclinical studypreconditioningreceptorresponsetargeted treatmenttraffickingtumortumor growthvaccine developmentvaccine efficacyyoung adult
项目摘要
ABSTRACT: Malignant primary brain tumors represent the most frequent cause of cancer death in children
and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is
uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In
contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T
cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the
brain. Dendritic cells (DCs) bearing tumor antigen can be delivered as a vaccine and migrate to the draining
lymph nodes (DLN) to trigger the formation of potent tumor-specific cytotoxic T lymphocytes (CTLs) capable of
eradicating tumor while leaving normal tissue unharmed. However, despite individual cases of remarkable
patient responses to antitumor DC vaccination, overall objective responses in early phase clinical trials have
remained under 15%. The migration of vaccine-delivered DCs is low (~5%), and preclinical studies have
demonstrated that preconditioning the vaccine site with the inflammatory cytokines can increase DC migration
to the DLN and proportionately increase the magnitude of the antigen-specific T cell response. We
hypothesized that preconditioning the vaccine site with the recall antigens in Tetanus/diphtheria toxoid (Td)
would induce inflammation, increase DC migration, and elicit more consistently efficacious antitumor immunity.
In a recent study in patients with newly diagnosed GBM published in Nature, we demonstrated that unilaterally
preconditioning one vaccine site with Td resulted in increased bilateral DC migration to the DLNs and a
significant increase in progression free survival and OS - with three of the six Td treated patients living past 4.5
years. A recapitulative murine model corroborated these findings, demonstrating that Td preconditioning both
enhanced systemic DC migration to the DLNs and suppressed tumor growth in an antigen-dependent manner.
Examination of both patient and murine sera revealed that the chemokine (C-C motif) ligand 3 (CCL3) was the
only cytokine or chemokine significantly upregulated after Td preconditioning. Furthermore, in mice we
demonstrated that the systemic increase in DC migration after Td preconditioning is dependent upon CD4+
memory effector T cells (CD4Td−mem) and CCL3. However, recent pilot data from our laboratory indicate that the
CD4Td−mem are actually responsible for the production of CCL3, suggesting CCL3 serves as the primary driver
of the improved antigen-dependent immunity from Td preconditioning. We hypothesize that in addition to
enhancing the migration of DCs to the DLN, that CCL3 directly increases antigen-specific T cell magnitude and
functionality as well as immune cell trafficking to tumor. This proposal will mechanistically determine the
specific role of CCL3 in DC migration, antigen-specific T cell responses, as well as immune cell trafficking, and
will further assess if the antitumor efficacy of DC vaccination can be further enhanced by the use of exogenous
CCL3 as a vaccine-enhancing drug.
摘要:恶性原发性脑肿瘤是儿童癌症死亡的最常见原因
而且比肾癌和黑色素瘤的死亡人数还要多。胶质母细胞瘤(GBM)是
一致致死,并且目前的治疗是非特异性的,并且产生<15个月的中位总生存期。在
相比之下,免疫疗法承诺了一种精确的方法,大量证据表明T
细胞可以根除小鼠和人类中的大型,良好的肿瘤,即使肿瘤位于细胞内,
携带肿瘤抗原的树突状细胞(DC)可以作为疫苗递送并迁移到引流管。
淋巴结(DLN),以触发形成有效的肿瘤特异性细胞毒性T淋巴细胞(CTL),
根除肿瘤而不伤害正常组织。然而,尽管个别案例引人注目
患者对抗肿瘤DC疫苗接种的反应,早期临床试验中的总体客观反应,
低于15%。疫苗递送的DC的迁移率低(~5%),临床前研究表明,
表明用炎性细胞因子预处理疫苗部位可以增加DC迁移
与DLN结合,并成比例地增加抗原特异性T细胞应答的幅度。我们
假设用破伤风/白喉类毒素(Td)中的回忆抗原预处理疫苗部位
将诱导炎症,增加DC迁移,并引发更一致有效的抗肿瘤免疫。
在最近发表在《自然》杂志上的一项针对新诊断GBM患者的研究中,我们证明了单方面
用Td预处理一个疫苗位点导致双侧DC向DLN的迁移增加,
无进展生存期和OS显著增加-6例Td治疗患者中有3例存活超过4.5年
年一个概括性的小鼠模型证实了这些发现,表明Td预处理,
增强系统性DC向DLN的迁移并以抗原依赖性方式抑制肿瘤生长。
对患者和小鼠血清的检查显示,趋化因子(C-C基序)配体3(CCL 3)是趋化因子受体。
只有细胞因子或趋化因子在Td预处理后显著上调。此外,在小鼠中,
表明Td预处理后DC迁移的全身性增加依赖于CD 4 +
记忆效应T细胞(CD 4 Td − T)和CCL 3。然而,我们实验室最近的试验数据表明,
CD 4 Td − T实际上负责CCL 3的产生,这表明CCL 3是主要的驱动因素。
Td预处理改善的抗原依赖性免疫。我们假设除了
增强DC向DLN的迁移,CCL 3直接增加抗原特异性T细胞数量,
功能性以及免疫细胞向肿瘤的运输。该提案将机械地确定
CCL 3在DC迁移、抗原特异性T细胞应答以及免疫细胞运输中的特异性作用,以及
将进一步评估DC疫苗接种的抗肿瘤功效是否可以通过使用外源性免疫抑制剂来进一步增强。
CCL 3作为疫苗增强药物。
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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JOHN H. SAMPSON其他文献
JOHN H. SAMPSON的其他文献
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{{ truncateString('JOHN H. SAMPSON', 18)}}的其他基金
Project 1: Targeting cytomegalovirus antigens in glioblastoma with regulatory T cell depletion
项目 1:通过消除调节性 T 细胞来靶向胶质母细胞瘤中的巨细胞病毒抗原
- 批准号:
10006177 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
Clinical Brain Tumor Development of a Cytomegalovirus-targeted Therapeutic with Vaccine pre-conditioning to Validate Novel Predictors of Vaccine Efficacy
通过疫苗预处理进行巨细胞病毒靶向治疗的临床脑肿瘤开发,以验证疫苗功效的新预测因子
- 批准号:
10310436 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
Project 1: Targeting cytomegalovirus antigens in glioblastoma with regulatory T cell depletion
项目 1:通过消除调节性 T 细胞来靶向胶质母细胞瘤中的巨细胞病毒抗原
- 批准号:
10246884 - 财政年份:2018
- 资助金额:
$ 34.78万 - 项目类别:
CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy
CCL3 作为一种增强脑肿瘤治疗的发育疗法
- 批准号:
10055778 - 财政年份:2016
- 资助金额:
$ 34.78万 - 项目类别:
Human EGFRvIII-specific BiTE for the treatment of Glioblastoma
人 EGFRvIII 特异性 BiTE 用于治疗胶质母细胞瘤
- 批准号:
9750830 - 财政年份:2015
- 资助金额:
$ 34.78万 - 项目类别:
Human EGFRvIII-specific BiTE for the treatment of Glioblastoma
人 EGFRvIII 特异性 BiTE 用于治疗胶质母细胞瘤
- 批准号:
9095464 - 财政年份:2015
- 资助金额:
$ 34.78万 - 项目类别:
Human EGFRvIII-specific BiTE for the treatment of Glioblastoma
人 EGFRvIII 特异性 BiTE 用于治疗胶质母细胞瘤
- 批准号:
8803629 - 财政年份:2015
- 资助金额:
$ 34.78万 - 项目类别:
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