Optimizing CAR T Cell Therapy
优化 CAR T 细胞疗法
基本信息
- 批准号:9338138
- 负责人:
- 金额:$ 37.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdolescenceAdoptive TransferAdverse effectsB lymphocyte-induced maturation protein 1B lymphoid malignancyB-LymphocytesBiologyCD19 geneCD8B1 geneCell TherapyCellsChemicalsChildChronicClinicClinical DataClinical TrialsDNA MethylationDevelopmentDimerizationDisease remissionDrug RegulationsDrug usageEngineeringEnsureEpigenetic ProcessFDA approvedFrequenciesFutureGene ExpressionGene Expression ProfilingGenerationsGenesGenetic TranscriptionGlobal ChangeGoalsHematopoietic Stem Cell TransplantationHistonesHumanIL6 geneImmunotherapyIn VitroInfusion proceduresInterleukin-6LifeLongevityMalignant - descriptorMalignant NeoplasmsMature T-LymphocyteMediatingMembraneMemoryModificationMusPathway interactionsPatientsPharmaceutical PreparationsPhenotypePluripotent Stem CellsPositioning AttributeProductionRecurrenceSafetySepsis SyndromeSignal TransductionSourceT cell differentiationT cell therapyT memory cellT-LymphocyteTestingTherapeuticTherapeutic EffectThymus GlandTransgenesTranslatingbasecancer therapychemoradiationchemotherapychimeric antigen receptorclinically relevantcytokinedevelopmental plasticitydimerepigenomeexhaustimprovedimproved outcomein vivoleukemia/lymphomaneoplasm immunotherapynovelnovel strategiespre-clinicalpreventpublic health relevancereceptorreceptor bindingresponsetranscription factortumorvirtual
项目摘要
Abstract: Our goal is to develop improved approaches for safe adoptive transfer of genetically modified T
cells. While transfer of anti-human CD19SFv chimeric antigen receptor (hCD19-CAR) expressing T cells have
provided dramatic effects in CD19+ B lymphoid malignancies, complications include prolonged B cell aplasia
and fatal severe systemic inflammatory response syndrome. We propose to solve these complications by using
a novel approach to regulate CAR function in vivo using an FDA approved drug at sub-therapeutic
concentrations. Tstem memory (Tsm) cells have the highest potency for anti-tumor responses due to their in
vivo longevity. Expanded CAR+ T cells lose Tnaive and Tsm phenotypes. We hypothesize that strategies to
retain or drive the Tsm state of CAR-T cells will improve outcomes. Human T cells have been reprogrammed
into inducible pluripotent stem cells (IPSCs) that can be readily genetically modified and re-differentiated into
mature T cells. We hypothesize that Tsm generated IPSCs can provide a virtually limitless source of long-
lasting Tsm CAR T cells and that starting IPSC generation from Tsm cell state will retain the epigenetic
landscape and developmental plasticity of Tsm cells in the final CAR-T cell product. Expanded T cells
differentiate into Teffectors or exhausted T cells, associated with profound, global changes in gene expression.
The transcription factor (TF) Bcl6 is expressed at high levels in CD8 Tsm, decreasing with progressive
differentiation, while Prdm1 expression reciprocally increases. We hypothesize that inducing high Bcl6 and loss
of Blimp-1 protein in IPSC T cell progeny will optimize Tsm CAR efficacy. Additional control is mediated by the
epigenome. We will use a combination of epigenetic and transcription analysis of Tsm, IPSC and T-IPSC
progeny to identify novel TFs that regulate the differentiation of Tsm from T-IPSC progeny. Specific aims will
test the hypotheses that: 1. Drug regulation of anti-hCD19SFv CAR in T cells can clear malignant CD19 B cells
by dimerizing receptors for an SFv with one containing an intracellular signaling domain (1A) and CAR
persistence is not fully dependent upon tumor- or host- derived B cell antigenic signals (1B). Competitor drug
infusion can rapidly halt CAR signaling by precluding dimerization, minimizing side-effects (1C); 2. Human Tsm
cells can be reprogrammed into IPSCs to provide a self-renewable, regulated anti-CD19 SFv CAR-Tsm cells
for adoptive tumor immunotherapy (2A). IPSCs can be induced to express a TF profile (bcl6hi; prdm1lo)
facilitating re-differentiated, ex vivo expanded Tsm CAR T cells to retain a non-senescent state (2B); 3.
Integrated analysis of gene expression, epigenetic analysis and TF “foot-printing” during in vitro Tsm
differentiation will identify (3A) and validate (3B) essential regulators of the Tsm state to optimize Tsm based
CAR therapy. These 3 aims will create an “off-the-shelf” product for CAR Tsm T cell therapy that can overcome
critical side-effects of CAR therapy and identify and validate key, novel TFs that will guide the optimization of
CAR therapy for future clinical trials in this PPG and establish a new paradigm of cancer treatment.
摘要:我们的目标是为转基因T细胞的安全收养转移开发改进的方法
细胞。而转移抗人CD19SFv嵌合抗原受体(hCD19-CAR)表达的T细胞
在CD19+B淋巴系恶性肿瘤中提供显著效果,并发症包括延长B细胞再生障碍性贫血
和致命的严重全身性炎症反应综合征。我们建议使用以下方法来解决这些并发症
在亚治疗阶段使用FDA批准的药物调节体内CAR功能的新方法
浓度。T细胞记忆(TSM)细胞因其自身的功能而具有最高的抗肿瘤反应能力
活体长寿。扩增的CAR+T细胞失去Tnaive和Tsm表型。我们假设战略是为了
保留或驱动CAR-T细胞的TSM状态将改善预后。人类T细胞被重新编程
转化为可诱导的多潜能干细胞(IPSCs),可以很容易地进行基因改造并重新分化为
成熟的T细胞。我们假设TSM产生的IPSC可以提供一个几乎无限的长期来源-
持续TSM CAR T细胞和从TSM细胞状态开始产生IPSC将保留表观遗传学
最终CAR-T细胞产物中TSM细胞的形态和发育可塑性。扩增的T细胞
分化为T效应细胞或精疲力竭的T细胞,与基因表达的深刻、全球变化有关。
转录因子(Tf)bcl6在CD8型TSM中高水平表达,随病变进展而降低。
分化程度越高,Prdm1表达水平越高。我们假设导致高bcl6和损失
在IPSC T细胞后代中表达Blimp-1蛋白将优化TSM CAR的疗效。额外的控制由
表观基因组。我们将结合TSM、IPSC和T-IPSC的表观遗传学和转录分析
鉴定调控TSM和T-iPSC子代分化的新的转录因子。具体的目标将
验证以下假设:1.药物调节T细胞中抗hCD19SFv CAR可以清除恶性CD19 B细胞
通过将SFV的受体与含有细胞内信号域(1A)和CAR的受体二聚化
持久性并不完全依赖于肿瘤或宿主来源的B细胞抗原信号(1B)。竞争对手药物
输液可以通过阻止二聚化迅速停止CAR信号,将副作用降至最低(1C);2.人TSM
细胞可以被重新编程为IPSCs,以提供自我更新的、受调节的抗CD19 SFV CAR-TSM细胞
用于过继肿瘤免疫治疗(2A)。诱导IPSCs表达转铁蛋白(bcl6hi;prdm1lo)
促进再分化、体外扩增的TSM CAR T细胞保持非衰老状态(2B);
体外TSM中基因表达、表观遗传分析和转铁蛋白“足迹”的综合分析
差异化将识别(3A)和验证(3B)TSM状态的基本调节器,以基于
汽车疗法。这3个目标将为CAR TSM T细胞疗法创造一种现成的产品,可以克服
汽车疗法的严重副作用,并确定和验证关键的、新颖的TF,将指导优化
CAR疗法为今后的临床试验奠定了基础,并建立了癌症治疗的新范式。
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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Bruce R Blazar其他文献
Challenges and solutions for cellular therapy development in autoimmune diseases
自身免疫性疾病中细胞治疗发展的挑战与解决方案
- DOI:
10.1016/s2665-9913(24)00274-1 - 发表时间:
2024-11-01 - 期刊:
- 影响因子:16.400
- 作者:
Elizabeth R Volkmann;John Varga;Bruce R Blazar;Steven Z Pavletic - 通讯作者:
Steven Z Pavletic
Five-Year Outcomes of the “Abatacept Combined with a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease (GVHD) Prophylaxis: A Randomized Controlled Trial” (‘ABA2‘)
- DOI:
10.1182/blood-2024-205130 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Lev Gorfinkel;Muna Qayed;Brandi Bratrude;Kayla Betz;Kyle Hebert;Sung W. Choi;Jeffrey Davis;Christine Duncan;Roger H. Giller;Michael S. Grimley;Andrew Harris;David A Jacobsohn;Nahal Lalefar;Nosha Farhadfar;Michael A. Pulsipher;Shalini Shenoy;Aleksandra Petrovic;Kirk R. Schultz;Gregory Yanik;Bruce R Blazar - 通讯作者:
Bruce R Blazar
IL-33 Induces Paneth Cell Production of EGF and Soluble ST2, Regulating Epithelial Regeneration after Intestinal Injury
- DOI:
10.1182/blood-2023-191189 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Marco Calafiore;YA-Yuan Fu;Paola Vinci;Viktor Arnhold;Winston Chang;Suze Jansen;Anastasiya Egorova;Shuichiro Takashima;Jason Kuttiyara;Takahiro Ito;Jonathan Serody;Susumu Nakae;Heth Turnquist;Johan van Es;Hans Clevers;Caroline A. Lindemans;Bruce R Blazar;Alan M. Hanash - 通讯作者:
Alan M. Hanash
Cyclosporine and Voclosporin Resistant Immune Effector Cells to Improve Outcomes after Stem Cell Transplantation
- DOI:
10.1182/blood-2023-180218 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Holly Wobma;Jiayi Dong;Francesca Alvarez Calderon;Xianliang Rui;Katherine Michaelis;Bruce R Blazar;Victor Tkachev;Ulrike Gerdemann;Leslie Kean - 通讯作者:
Leslie Kean
Mitochondrial Pyruvate Carrier Inhibition Mitigates Murine Chronic Graft Versus Host Disease By Attenuating the Germinal Center Reaction
- DOI:
10.1182/blood-2023-185200 - 发表时间:
2023-11-02 - 期刊:
- 影响因子:
- 作者:
Fathima A Mohamed;Stephanie Y Rhee;Joanna Ly;Ethan G Aguilar;Haley Melin;Peter T Sage;Tanner Schumacher;Govindarajan Thangavelu;Michael C Zaiken;Juan Liu;Venkatram Mereddy;Jason W Locasale;Bruce R Blazar - 通讯作者:
Bruce R Blazar
Bruce R Blazar的其他文献
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{{ truncateString('Bruce R Blazar', 18)}}的其他基金
University of Minnesota Clinical and Translational Science Institute (UMN CTSI)
明尼苏达大学临床与转化科学研究所 (UMN CTSI)
- 批准号:
10763967 - 财政年份:2023
- 资助金额:
$ 37.93万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10560605 - 财政年份:2021
- 资助金额:
$ 37.93万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10092348 - 财政年份:2021
- 资助金额:
$ 37.93万 - 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
- 批准号:
10348683 - 财政年份:2021
- 资助金额:
$ 37.93万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
10305635 - 财政年份:2019
- 资助金额:
$ 37.93万 - 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
- 批准号:
10656502 - 财政年份:2019
- 资助金额:
$ 37.93万 - 项目类别:
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