Linking insertional mutagenesis and cell function to improve CAR T cell therapy
将插入突变与细胞功能联系起来以改善 CAR T 细胞疗法
基本信息
- 批准号:10640072
- 负责人:
- 金额:$ 59.21万
- 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:2019-06-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAdult Acute Lymphocytic LeukemiaAllelesAnimal ModelAntigensApoptosisAutomobile DrivingB lymphoid malignancyBioinformaticsBiological AssayCAR T cell therapyCD19 geneCancer PatientCell Culture TechniquesCell physiologyCellsCessation of lifeChildhood Acute Lymphocytic LeukemiaChronic Lymphocytic LeukemiaClinicalClonal ExpansionClone CellsClustered Regularly Interspaced Short Palindromic RepeatsCustomCyclic AMPDNADataData SetDisease remissionEngineeringEnzymesEventFailureGene ModifiedGene TargetingGenesGenomeGoalsHandHumanHuman GenomeInositol PhosphatesInsertional MutagenesisLentivirus VectorLinkMalignant NeoplasmsMethodsMultiple MyelomaMutagensOutputPathway interactionsPatientsPhosphotransferasesPositioning AttributeProliferatingProteinsPublishingReagentReporter GenesReportingRoleRouteSamplingSeriesSolid NeoplasmSpecific qualifier valueSystemT cell differentiationT cell therapyT-Cell ProliferationT-LymphocyteTGFBR2 geneTestingTherapeuticTimeTranslatingTumor AntigensValidationcancer cellcancer immunotherapycancer therapycell growthchimeric antigen receptorclinical developmentcohortdeep sequencingdemethylationengineered T cellsfollow-upgene functiongenetic manipulationhigh riskimprovedimproved outcomeintegration sitekinase inhibitorlentiviral integrationleukemialongitudinal analysismouse modelpersonalized cancer therapyreceptorrelapse riskresponsesuccesstissue culturetumorvector
项目摘要
Summary
Chimeric antigen receptor-engineered T cells (CAR T cells) provide a breakthrough for personalized cancer
therapy. In this approach, a gene encoding a CAR targeting tumor antigens is delivered into patient T-cells ex
vivo using a lentiviral vector, then cells reinfused into patients. The engineered CAR T cells expand in the patient
and attack and destroy tumor antigen-positive cancer cells. Robust clinical responses are seen with CAR T cell
therapy in some leukemias such as pediatric acute lymphocytic leukemia (ALL), but lower rates of response in
adult ALL, chronic lymphocytic leukemia (CLL) and multiple myeloma. One consequence of integration of a CAR-
encoding lentiviral vector in patient T cells is local disruption of the host genome. We recently published an
example where the resulting insertional mutagenesis bolstered successful therapy--patient T-cell expansion was
associated with an integration event in TET2, which encodes an enzyme involved in CpG demethylation, and
this was mechanistically linked with enhanced T cell function and durable remission. Here we take advantage of
data from insertional mutagenesis of patient CAR T cells to identify genes and pathways of particular importance
for effective anti-tumor activity. TGFBR2 provides a second example of where insertional mutagenesis was
associated with expansion of CAR T cells, and separate studies have also implicated reduced function of this
gene as associated with improved CART function. Intense efforts are now under way to modulate both of these
pathways to enhance therapeutic success. We have completed longitudinal analysis of integration site
distributions in 40 CAR T-treated subjects, targeting both ALL and CLL, and find numerous examples of clonal
expansions in patients successfully responding to therapy, providing a unique window on CAR T cell function.
We have in hand samples from another 266 subjects, some of whom are responders showing long term
persistence of CAR T cells. We have further devised a series of assays in cell culture and mouse models to
modulate activity of targeted genes and characterize CAR T cell proliferation and anti-tumor activity. Thus we
propose to investigate these genes and pathways in detail and develop means for manipulating them clinically.
We propose the following Specific Aims: Aim 1. Elucidate the rules governing superior CAR T cell proliferation
and persistence taking advantage of lentiviral integration as an insertional mutagen. Aim 2. Carry out functional
analyses of genes implicated in vector driving of CAR T cells to identify proteins and pathways important for CAR
T proliferation, persistence and anti-tumor activity. The output of this project will be methods for manipulating
genes and pathways important for effective CAR T proliferation and function, which will then be taken directly
into clinical development.
总结
嵌合抗原受体工程化T细胞(CAR T细胞)为个性化癌症提供了突破
疗法在这种方法中,编码靶向肿瘤抗原的CAR的基因被递送到患者T细胞中,
体内使用慢病毒载体,然后将细胞重新输注到患者体内。工程化CAR T细胞在患者体内扩增
攻击并摧毁肿瘤抗原阳性癌细胞。使用CAR T细胞观察到稳健的临床应答
治疗某些白血病,如小儿急性淋巴细胞白血病(ALL),但反应率较低,
成人ALL、慢性淋巴细胞白血病(CLL)和多发性骨髓瘤。整合CAR的一个结果-
在患者T细胞中的编码慢病毒载体是宿主基因组的局部破坏。我们最近发布了一份
由此产生的插入诱变支持成功治疗的实例-患者T细胞扩增被
与TET 2中的整合事件相关,TET 2编码参与CpG去甲基化的酶,和
这在机制上与T细胞功能增强和持久缓解有关。在这里,我们利用
来自患者CAR T细胞的插入诱变的数据,以鉴定特别重要的基因和途径
有效的抗肿瘤活性。TGFBR 2提供了插入诱变的第二个例子。
与CAR T细胞的扩增相关,并且单独的研究也暗示了这种功能的降低。
与改善的CART功能相关的基因。目前正在加紧努力调整这两个方面
提高治疗成功率的途径。我们已经完成了整合位点的纵向分析
在40名CAR T治疗的受试者中,靶向ALL和CLL,并发现了许多克隆的例子。
成功对治疗产生反应的患者的扩增,为CAR T细胞功能提供了独特的窗口。
我们手头有来自另外266名受试者的样本,其中一些人是反应者,
CAR T细胞的持久性。我们进一步设计了一系列细胞培养和小鼠模型的试验,
调节靶基因的活性并表征CAR T细胞增殖和抗肿瘤活性。因此我们
我们建议详细研究这些基因和途径,并开发出在临床上操纵它们的方法。
我们提出以下具体目标:目标1。阐明控制上级CAR T细胞增殖的规则
以及利用慢病毒整合作为插入诱变剂的持久性。目标2.进行功能
分析与CAR T细胞的载体驱动有关的基因,以鉴定对CAR重要的蛋白质和途径
T细胞增殖、持久性和抗肿瘤活性。该项目的输出将是用于操作
对于有效的CAR T增殖和功能重要的基因和途径,然后将直接
进入临床开发。
项目成果
期刊论文数量(1)
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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Frederic D Bushman其他文献
The enigmatic roles of emAnelloviridae/em and emRedondoviridae/em in humans
人类中的 emAnelloviridae/em 和 emRedondoviridae/em 的神秘作用
- DOI:
10.1016/j.coviro.2022.101248 - 发表时间:
2022-08-01 - 期刊:
- 影响因子:5.100
- 作者:
Louis J Taylor;Emma L Keeler;Frederic D Bushman;Ronald G Collman - 通讯作者:
Ronald G Collman
HTLV-1 clonality during chronic infection and BLV clonality during primary infection
- DOI:
10.1186/1742-4690-8-s1-a185 - 发表时间:
2011-06-06 - 期刊:
- 影响因子:3.900
- 作者:
Nicolas A Gillet;Carol Hlela;Tine Verdonck;Eduardo Gotuzzo;Daniel Clark;Sabrina Rodriguez;Nirav Malani;Anat Melamed;Niall Gormley;Richard Carter;David Bentley;Charles Berry;Frederic D Bushman;Graham P Taylor;Luc Willems;Charles R M Bangham - 通讯作者:
Charles R M Bangham
Bromodomain and extra-terminal (BET) proteins target Moloney murine leukemia virus integration to transcription start sites
- DOI:
10.1186/1742-4690-10-s1-o20 - 发表时间:
2013-09-19 - 期刊:
- 影响因子:3.900
- 作者:
Jan De Riick;Christine de Kogel;Jonas Demeulemeester;Sofie Vets;Nirav Malani;Frederic D Bushman;Katrien Busschots;Steven Husson;Rik Gijsbers;Zeger Debyser - 通讯作者:
Zeger Debyser
Frederic D Bushman的其他文献
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{{ truncateString('Frederic D Bushman', 18)}}的其他基金
mVACS--mRNA Vaccines for C. difficile Suppression
mVACS--用于抑制艰难梭菌的 mRNA 疫苗
- 批准号:
10625573 - 财政年份:2023
- 资助金额:
$ 59.21万 - 项目类别:
Preserving Genome Integrity In AAV-Mediated Gene Therapy
在 AAV 介导的基因治疗中保持基因组完整性
- 批准号:
10338480 - 财政年份:2022
- 资助金额:
$ 59.21万 - 项目类别:
Preserving Genome Integrity In AAV-Mediated Gene Therapy
在 AAV 介导的基因治疗中保持基因组完整性
- 批准号:
10558679 - 财政年份:2022
- 资助金额:
$ 59.21万 - 项目类别:
Linking insertional mutagenesis and cell function to improve CAR T cell therapy
将插入突变与细胞功能联系起来以改善 CAR T 细胞疗法
- 批准号:
10398224 - 财政年份:2019
- 资助金额:
$ 59.21万 - 项目类别:
Linking insertional mutagenesis and cell function to improve CAR T cell therapy
将插入突变与细胞功能联系起来以改善 CAR T 细胞疗法
- 批准号:
10158019 - 财政年份:2019
- 资助金额:
$ 59.21万 - 项目类别:














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