Novel Strategies to Treat Diffuse Midline Glioma with CAR T Cell Therapy
利用 CAR T 细胞疗法治疗弥漫性中线胶质瘤的新策略
基本信息
- 批准号:10284722
- 负责人:
- 金额:$ 22.3万
- 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:2021-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adenovirus VectorAffinityAnatomyAntigen PresentationAntigen ReceptorsAntigen TargetingAntigen-Presenting CellsAntigensB-LymphocytesBrain NeoplasmsBrain StemCAR T cell therapyCD19 geneCD276 geneCD80 geneCellsChemosensitizationClinicalCombined Modality TherapyComplementCytolysisDHFR geneDataDendritic cell activationDiffuseDiffuse intrinsic pontine gliomaDiseaseEngineeringEscherichia coliGenetic EngineeringGliomaGoalsH3 K27M mutationHematologyImmuneImmune systemImmunocompetentImmunotherapeutic agentImmunotherapyInflammationInterleukin-12LicensingLocationMediatingModelingNormal tissue morphologyOncolyticOncolytic virusesOutcomePatientsProductionPropertyReportingResearch Project GrantsSafetySignal TransductionSolid NeoplasmStimulusT cell responseT-LymphocyteTNFRSF5 geneTNFSF5 geneTechnologyTestingTherapeuticTherapeutic EffectTissuesToxic effectTranslationsTropismTumor AntigensUp-RegulationViralVirusVirus Activationcancer therapychimeric antigen receptorchimeric antigen receptor T cellscombinatorialcytokineepidermal growth factor receptor VIIIexpression vectorinsightmelanomaneoplasticneoplastic cellnovelnovel strategiesoncolysisoncolytic adenovirusoncolytic vectorpre-clinicalrecruitresearch clinical testingresponsesafety testingsubcutaneoustumortumor microenvironmentvector
项目摘要
PROJECT SUMMARY
Although chimeric antigen receptor (CAR) T cells have been remarkably successful in the hematologic setting,
identification of truly tumor specific antigens for many solid tumor indications has limited broad translation. Two
targets have been considered for Diffuse Midline Glioma H3 K27M-mutant tumors (previously Diffuse Intrinsic
Pontine Glioma (DIPG)), however as neither are exclusively restricted to neoplastic tissue, safety concerns
exist with respect to on-target, off-tumor toxicity. Moreover, ancillary treatment meant to boost CAR T function
to overcome a constellation of immune suppressive mechanisms associated with the solid tumor
microenvironment also has the potential to exacerbate the problem. Our group has conducted extensive
preclinical characterization of oncolytic viruses and has demonstrated them to be a highly effective
immunotherapeutic agents for the treatment of cancer. We propose to leverage the tumor tropism of ∆24
oncolytic adenovirus to deliver a CAR target along with CD40L. Our preliminary data indicates that oncolytic
Ad∆24-CD40L provides a significant therapeutic advantage in a GL261 glioma model as a monotherapy, and
further, can potentiate CD19 CAR T therapy in a proof of concept combination setting against subcutaneous
B16-CD19 tumors. The goal of this proposal is to develop a dual therapy approach which builds on direct
tumor cell viral oncolysis and CAR T cytolysis, enhanced CAR T cell recruitment/activation by virus-mediated
inflammation, and importantly, CD40L-mediated mobilization of endogenous antigen presenting cells, B cells
and T cells. We will engineer an oncolytic vector to deliver titratable levels of CD40L using the E. coli DHFR
destabilizing domain, and an intracellularly truncated signaling-dead EGFRvIII molecule to be used in
conjunction with safety tested EGFRvIII CAR T cells (Aim1). The safety and efficacy of the OV-CAR T
approach will be evaluated in a genetically engineered immunocompetent model of DIPG (Aim 2). This project
is expected to provide novel insight into how CD40L can mobilize an endogenous B cell and T cell response
and support CAR T therapy. Together, we hope to capitalize on the properties of designer oncolytic viruses to
more broadly enable the use of CAR T cell therapy in solid tumors, and in particular apply existing safety
tested immunotherapies to a devastating and urgent unmet clinical need.
项目摘要
尽管嵌合抗原受体(CAR)T细胞在血液学环境中已经非常成功,
对许多实体瘤适应症的真正肿瘤特异性抗原的鉴定限制了广泛的应用。两
已经考虑了用于弥漫性中线胶质瘤H3 K27 M突变型肿瘤的靶点(先前为弥漫性固有型
脑桥胶质瘤(DIPG)),但由于两者均不限于肿瘤组织,因此存在安全性问题
存在靶向、非肿瘤毒性。此外,辅助治疗意味着增强CAR T功能,
以克服与实体瘤相关的一系列免疫抑制机制,
微环境也有可能加剧这一问题。我们的团队进行了广泛的
溶瘤病毒的临床前表征,并已证明它们是一种非常有效的
用于治疗癌症的免疫抑制剂。我们建议利用肿瘤嗜性24
用溶瘤腺病毒递送CAR靶标沿着CD 40 L。我们的初步数据表明,
Ad CD 24-CD 40 L作为单一疗法在GL 261神经胶质瘤模型中提供了显著的治疗优势,并且
此外,可以在概念验证组合环境中增强CD 19 CAR T疗法,
B16-CD 19肿瘤。该提案的目标是开发一种双重治疗方法,
肿瘤细胞病毒溶瘤和CAR T细胞溶解,通过病毒介导的增强CAR T细胞募集/激活
炎症,重要的是,CD 40 L介导的内源性抗原递呈细胞(B细胞)动员
和T细胞。我们将设计一种溶瘤载体,使用E.大肠杆菌DHFR
去稳定化结构域和细胞内截短的信号死亡EGFRvIII分子,
与安全性测试的EGFRvIII CAR T细胞(Aim 1)结合。OV-CAR T的安全性和有效性
方法将在DIPG的基因工程免疫活性模型中进行评估(目的2)。这个项目
有望为CD 40 L如何动员内源性B细胞和T细胞应答提供新的见解
支持CAR T疗法我们希望共同利用设计溶瘤病毒的特性,
更广泛地使CAR T细胞疗法在实体瘤中的使用成为可能,特别是将现有的安全性
测试的免疫疗法,以一个毁灭性的和紧迫的未满足的临床需求。
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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Richard G. Vile其他文献
Viral fusogenic membrane glycoproteins are a new class of therapeutic genes for the treatment of hepatocellular carcinoma (HCC)
- DOI:
10.1016/s0016-5085(00)85751-0 - 发表时间:
2000-04-01 - 期刊:
- 影响因子:
- 作者:
Hajime Higuchi;Steven F. Bronk;Richard G. Vile;Gregory J. Gores - 通讯作者:
Gregory J. Gores
Richard G. Vile的其他文献
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{{ truncateString('Richard G. Vile', 18)}}的其他基金
Characterizing the role of CSDE1 as a critical co-factor for VSV replication.
描述 CSDE1 作为 VSV 复制关键辅助因子的作用。
- 批准号:
10650485 - 财政年份:2023
- 资助金额:
$ 22.3万 - 项目类别:
Re-purposing Oncolytic Virotherapy to Re-invigorate CAR T Cell Therapy for Solid Tumors.
重新调整溶瘤病毒疗法以重振实体瘤 CAR T 细胞疗法。
- 批准号:
10578864 - 财政年份:2022
- 资助金额:
$ 22.3万 - 项目类别:
Novel Strategies to Treat Diffuse Midline Glioma with CAR T Cell Therapy
利用 CAR T 细胞疗法治疗弥漫性中线胶质瘤的新策略
- 批准号:
10412129 - 财政年份:2021
- 资助金额:
$ 22.3万 - 项目类别:
Enhancing Therapy of Primary and Recurrent Tumors With Systemic Oncolytic Virus
用全身溶瘤病毒增强原发性和复发性肿瘤的治疗
- 批准号:
8687777 - 财政年份:2014
- 资助金额:
$ 22.3万 - 项目类别:
Enhancing Therapy of Primary and Recurrent Tumors With Systemic Oncolytic Virus
用全身溶瘤病毒增强原发性和复发性肿瘤的治疗
- 批准号:
9047245 - 财政年份:2014
- 资助金额:
$ 22.3万 - 项目类别:
Enhancing Systemic Delivery of Oncolytic Viruses for Cancer Therapy
增强溶瘤病毒的全身递送用于癌症治疗
- 批准号:
8387981 - 财政年份:2009
- 资助金额:
$ 22.3万 - 项目类别:
Enhancing Systemic Delivery of Oncolytic Viruses for Cancer Therapy
增强溶瘤病毒的全身递送用于癌症治疗
- 批准号:
7993072 - 财政年份:2009
- 资助金额:
$ 22.3万 - 项目类别:
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