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
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 26.27万 - 项目类别:
Research Grant