Project 4 Treatment of Advanced Ovarian Cancer Using Gene-Edited NK CAR Cells
项目4 使用基因编辑的NK CAR细胞治疗晚期卵巢癌
基本信息
- 批准号:10268766
- 负责人:
- 金额:$ 26.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2026-08-30
- 项目状态:未结题
- 来源:
- 关键词:Activated Natural Killer CellAddressAdultAffectAllogenicAnimal ModelAntigen TargetingAntigensAscitesB lymphoid malignancyBiometryBloodCAR T cell therapyCD19 geneCISH geneCRISPR/Cas technologyCell LineCell SurvivalCell TherapyCellsCellular biologyCharacteristicsChromosomal InstabilityChronicClinicClinicalClinical TrialsClinical Trials DesignClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCorrelative StudyCytokine SignalingDataDevelopmentDiagnosisDisadvantagedDoseElectroporationEngineeringEpithelial ovarian cancerExcisionFutureGenesGeneticGenetic EngineeringGoalsGuide RNAHumanHypersensitivityImmuneImmunotherapyInterleukin-15Intracellular Signaling ProteinsK-562Knock-inKnock-outKnockout MiceLearningLigandsMalignant NeoplasmsMalignant neoplasm of ovaryMaximum Tolerated DoseMeasuresMembraneMethodsModificationMutateMutationNK Cell ActivationNK cell therapyNatural Killer CellsNeoplasm MetastasisPARP inhibitionPatientsPeritonealPhase I Clinical TrialsPhase I/II TrialPhysiologicalPreclinical TestingProcessProteinsProtocols documentationRNAReceptor CellReceptor GeneRecombinant adeno-associated virus (rAAV)RecurrenceRefractoryResearchResistanceResourcesSignal PathwaySignal TransductionSiteSolid NeoplasmSpecificitySurfaceSurvival RateT cell therapyT-LymphocyteTechniquesTestingToxic effectTumor AntigensVascular Endothelial Growth FactorsViralWomanWorkarmbasecancer cellchimeric antigen receptorcytokinecytokine release syndromedesignengineered NK cellexhaustiongraft vs host diseaseimmune checkpoint blockadeimprovedimproved outcomein vitro testingin vivointerleukin-21mesothelinmolecular targeted therapiesnovelnovel therapeuticspatient derived xenograft modelperipheral bloodphase 1 designsprogramsresistance mechanismresponsesecondary outcomeside effectsuccesstherapy outcometumor microenvironmenttumor progression
项目摘要
ABSTRACT – PROJECT 4
Women diagnosed with advanced epithelial ovarian cancer (EOC) have a median 5-year survival rate of ~20%,
and recurrent EOC remains essentially incurable. Novel immunotherapies, including immune checkpoint
blockade and chimeric antigen receptor (CAR) T cell therapies have had some success, but response rates
have been typically below 20%. Similarly, the response rates to molecularly targeted therapies have been
limited, partly due to the lack of recurrently mutated targets and the high level of chromosomal instability
characteristic of EOC. Synthetic lethality via PARP inhibition and VEGF blockade have demonstrated some
benefit, but mechanisms of resistance have already surfaced for these new therapies. The long-term goal of
our research program is to develop highly effective immune cell-based therapies capable of eliminating
recurrent EOC. In Project 4, we will use advanced gene editing techniques that we have developed to produce
hyperfunctional Natural Killer (NK) cells for treating advanced EOC. We focus on NK cells because i) they do
not require antigen priming and ii) side effects, such as graft versus host disease and cytokine release
syndrome, are minimal compared to T cell therapy. We propose to make two fundamental alterations to human
NK cells obtained from healthy donors. The first genetic alteration removes an intracellular signaling protein
that dampens NK activation (the CISH gene) using a modified CRISPR/Cas9 protocol we have developed that
is highly effective in primary human NK cells. The second genetic alteration is to site-specifically integrate a
chimeric antigen receptor (CAR) gene that we have developed specifically for NK cells. This CAR NK targets
the mesothelin protein, a prevalent EOC tumor antigen. Our central hypothesis is that gene editing can be
used to overcome signaling inhibition and improve NK cell targeting, persistence and function, resulting in
improved therapeutic outcomes for women with advanced EOC. The work proposed in this project includes
generating and testing the gene edited NK cells for enhanced function by co-culturing with ovarian cancer cells
in vitro and testing in both cell line- and patient-derived xenograft models of EOC in vivo. The data from these
preclinical tests will be used to guide the design of the Phase I clinical trial using these gene-edited NK cells.
This project will determine whether gene-edited CAR NK cell immunotherapy in humans is safe and has the
potential to improve outcomes in the setting of recurrent EOC. In addition, what we learn from this study will
have the broader impact of potential future application to other malignancies, as the engineering techniques
can be quickly adapted to remove different negative regulators and to target other tumor antigens with NK-
specific CARs.
摘要-项目4
诊断为晚期上皮性卵巢癌(EOC)的女性中位5年生存率约为20%,
而复发性EOC基本上仍然无法治愈。新型免疫疗法,包括免疫检查点
阻断和嵌合抗原受体(CAR)T细胞疗法已经取得了一些成功,但反应率
通常低于20%。同样,分子靶向治疗的反应率也是
有限,部分原因是缺乏反复突变的靶点和高水平的染色体不稳定性。
EOC的特点。通过PARP抑制和VEGF阻断的合成致死性已经证明了一些
这些新疗法的好处,但耐药机制已经浮出水面。的长期目标
我们的研究计划是开发高效的免疫细胞疗法,
复发性EOC。在项目4中,我们将使用我们开发的先进基因编辑技术来生产
高功能性自然杀伤(NK)细胞用于治疗晚期EOC。我们专注于NK细胞,因为i)它们
不需要抗原引发和ii)副作用,例如移植物抗宿主病和细胞因子释放
与T细胞疗法相比,我们建议对人类进行两个根本性的改变,
从健康供体获得的NK细胞。第一个基因改变去除了一个细胞内信号蛋白
使用我们开发的改良CRISPR/Cas9方案抑制NK激活(CISH基因),
在原代人类NK细胞中非常有效。第二个基因改变是位点特异性整合一个
嵌合抗原受体(CAR)基因,我们已经开发了专门用于NK细胞。这款CAR NK靶向
间皮素蛋白,一种普遍的EOC肿瘤抗原。我们的核心假设是,基因编辑可以
用于克服信号传导抑制并改善NK细胞靶向、持久性和功能,
改善晚期EOC女性患者的治疗结果。本项目拟开展的工作包括
通过与卵巢癌细胞共培养产生并测试基因编辑的NK细胞的增强功能
在体外和体内在细胞系和患者来源的EOC异种移植模型中进行测试。这些数据
临床前试验将用于指导使用这些基因编辑的NK细胞的I期临床试验的设计。
该项目将确定人类基因编辑的CAR NK细胞免疫疗法是否安全,
在复发性EOC的情况下改善结局的潜力。此外,我们从这项研究中学到的东西将
具有更广泛的潜在未来应用于其他恶性肿瘤的影响,因为工程技术
可以快速适应去除不同的负调节因子,并靶向其他肿瘤抗原,
特定的汽车
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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Branden S Moriarity其他文献
Targeting the intracellular immune checkpoint CISH with CRISPR-Cas9-edited T cells in patients with metastatic colorectal cancer: a first-in-human, single-centre, phase 1 trial
在转移性结直肠癌患者中使用 CRISPR-Cas9 编辑的 T 细胞靶向细胞内免疫检查点 CISH:一项首次人体、单中心、1 期试验
- DOI:
10.1016/s1470-2045(25)00083-x - 发表时间:
2025-05-01 - 期刊:
- 影响因子:35.900
- 作者:
Emil Lou;Modassir S Choudhry;Timothy K Starr;Timothy D Folsom;Jason Bell;Blaine Rathmann;Anthony P DeFeo;Jihyun Kim;Nicholas Slipek;Zhaohui Jin;Darin Sumstad;Christopher A Klebanoff;Katherine Ladner;Akshat Sarkari;R Scott McIvor;Thomas A Murray;Jeffrey S Miller;Madhuri Rao;Eric Jensen;Jacob Ankeny;Branden S Moriarity - 通讯作者:
Branden S Moriarity
<em>In Vivo</em> Correction of a Genetically Humanized Fanconi Anemia Mouse Bone Marrow Failure Model Using Digital Editing Technologies
- DOI:
10.1182/blood-2024-210783 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Branden S Moriarity;Beau R Webber;Colette B Rogers;John E Wagner;Joseph J Peterson;Cassandra Butterbaugh;Paige Carlson - 通讯作者:
Paige Carlson
emIn Vivo/em Correction of a Genetically Humanized Fanconi Anemia Mouse Bone Marrow Failure Model Using Digital Editing Technologies
使用数字编辑技术在体内校正遗传人源化范可尼贫血小鼠骨髓衰竭模型
- DOI:
10.1182/blood-2024-210783 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:23.100
- 作者:
Branden S Moriarity;Beau R Webber;Colette B Rogers;John E Wagner;Joseph J Peterson;Cassandra Butterbaugh;Paige Carlson - 通讯作者:
Paige Carlson
FAS Ablation Confers Resistance to Allogeneic CAR-T Rejection By T Cells in Absence of NK Cell Sensitization
- DOI:
10.1182/blood-2024-207581 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Silvia Menegatti;Sheila Lopez-Cobo;Aurelien Sutra Del Galy;Jaime Fuentealba;Lisseth Silva;Laeticia Perrin;Sandrine Heurtebise-Chrétien;Valentine Pottez-Jouatte;Aurélie Darbois;Nina Burgdorf;Albane Simon;Marguerite Laprie-Santenac;Michael Saitakis;Bruce Wick;Beau R Webber;Branden S Moriarity;Olivier Lantz;Sebastian Amigorena;Laurie Menger - 通讯作者:
Laurie Menger
Branden S Moriarity的其他文献
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{{ truncateString('Branden S Moriarity', 18)}}的其他基金
Engineered B Cells as a Universal Platform for the Treatment of Enzymopathies
工程 B 细胞作为治疗酶病的通用平台
- 批准号:
10582595 - 财政年份:2020
- 资助金额:
$ 26.27万 - 项目类别:
Engineered B Cells as a Universal Platform for the Treatment of Enzymopathies
工程 B 细胞作为治疗酶病的通用平台
- 批准号:
10358566 - 财政年份:2020
- 资助金额:
$ 26.27万 - 项目类别:
Optimizing Gene Editing in Primary Human B Cells for Therapy and Research
优化人类原代 B 细胞中的基因编辑以用于治疗和研究
- 批准号:
9224508 - 财政年份:2017
- 资助金额:
$ 26.27万 - 项目类别:
Multiplex 'Conditional' Mice for Rapid and Affordable Pre-clinical Testing
多重“条件”小鼠用于快速且经济实惠的临床前测试
- 批准号:
9195708 - 财政年份:2015
- 资助金额:
$ 26.27万 - 项目类别:
Project 4 Treatment of Advanced Ovarian Cancer Using Gene-Edited NK CAR Cells
项目4 使用基因编辑的NK CAR细胞治疗晚期卵巢癌
- 批准号:
10452722 - 财政年份:2009
- 资助金额:
$ 26.27万 - 项目类别:
Project 4 Treatment of Advanced Ovarian Cancer Using Gene-Edited NK CAR Cells
项目4 使用基因编辑的NK CAR细胞治疗晚期卵巢癌
- 批准号:
10705051 - 财政年份:2009
- 资助金额:
$ 26.27万 - 项目类别:
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