Development of a treatment for durable remission of HIV using transposon engineered CAR-T and NK cells
Development of a treatment for durable remission of HIV using transposon engineered CAR-T and NK cells
批准号:
10599604
负责人:
Maria Constance Athanasiou
金额:
$30.65万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-12-07 至 2024-11-30
关键词:
AddressAllelesAllogenicAnimal ModelAnimalsAnti-Retroviral AgentsAntibody FormationAntigensApoptosisAutologousB-LymphocytesBLR1 geneBlood CellsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCXCL13 geneCancer PatientCell physiologyCellsCellular immunotherapyChronicClinical TrialsDevelopmentDevicesDiseaseDisease remissionEffectivenessEngineeringFemaleFlow CytometryGammaretrovirusHIVHIV InfectionsHIV therapyHIV-1HomingHumanImmuneImmune TargetingIndividualInfusion proceduresInvestigationLigandsLymphoidLymphoid TissueMacacaMacaca mulattaMediatingMethodsNK cell therapyNatural Killer CellsPatientsPharmaceutical PreparationsPhasePhenotypePilot ProjectsPrimatesProductionProteinsRNASIVT cell responseT cell therapyT-LymphocyteTherapeuticToxic effectUmbilical Cord BloodViralViral Load resultViral PhysiologyViral reservoirVirusVirus DiseasesVirus Replicationantiretroviral therapycellular transductionchemokine receptorchimeric antigen receptorchimeric antigen receptor T cellschronic infectioncytokine release syndromefightingimprovedin vivoindividualized medicineknock-downmalemigrationnovelprotein expressionreceptorresponsesafety assessmentsimian human immunodeficiency virustreatment strategyvector
中文摘要
项目摘要
MarPam Pharma旨在开发一次性治疗方法,以实现人类持久缓解
免疫缺陷病毒(艾滋病毒),之后患者将不再需要采取抗逆转录病毒治疗。我们
治疗是自体HIV特异性嵌合抗原受体(CAR)免疫细胞疗法,其采用
CXCR 5趋化因子受体作为导向抗HIV T细胞或抗HIV自然杀伤细胞(NK)的归巢装置
在淋巴B细胞滤泡中,大多数产生病毒的细胞
是在慢性感染的时候。病毒特异性CD 8 T细胞对HIV-1和HIV-2发挥有效的抗病毒活性。
猴免疫缺陷病毒(SIV),一种HIV的动物模型。然而,尽管有大量的CD 8 T细胞,
在HIV-1感染的人类和SIV感染的猕猴中,这些细胞不能完全抑制病毒的反应,
复制,可能是因为大多数HIV-1和SIV复制发生在CD 4 + T细胞集中在
次级淋巴组织中的B细胞滤泡,其中令人惊讶的是很少有病毒特异性CD 8 T细胞存在于感染的淋巴细胞中。
个体事实上,我们发现体内靶向病毒(v)RNA+细胞(E:T)的效应CTL水平低40倍。
与B细胞滤泡外相比,这可能是因为很少有病毒特异性CD 8 T细胞表达
毛囊归巢分子CXCR 5这些发现表明,HIV特异性CD 8 T细胞不能
完全抑制病毒复制可能是由于B细胞滤泡中缺乏病毒特异性CD 8 T细胞。为
绝大多数病毒产生细胞是位于次级淋巴组织中的CD 4 T细胞,并集中在
在慢性HIV和SIV感染期间,我们通过输注自体抗病毒药物靶向这些受感染的细胞,
慢性SIV感染恒河猴中的CAR/CXCR 5-T细胞。治疗的动物表现出成功的
CAR/CXCR 5-T细胞归巢至B细胞滤泡,CAR/CXCR 5-T细胞与B细胞滤泡直接接触的证据,
与未处理的动物相比,在处理的动物中vRNA+感染的细胞和降低的病毒载量。我们的飞行员
研究表明,治疗是安全和有效的。这些发现促使我们进一步完善
我们有希望的靶向CAR/CXCR 5-T细胞疗法,通过增强其疗效,并研究这是否
可以使用NK细胞开发靶向免疫细胞疗法。CAR-T和CAR-NK细胞疗法是
个体化疗法,修改患者自身的免疫细胞来对抗疾病; NK细胞疗法也有
作为使用同种异体细胞的现成治疗的潜力。该提案旨在优化
CAR/CXCR 5免疫细胞疗法的有效性。此外,我们的目标是生成和评估优化的
Car/CXCR 5-T和-NK细胞使用较便宜的生产方法。圆满完成拟议的
研究将导致II期IND启动灵长类动物研究,以评估T细胞和NK细胞的安全性和有效性。
细胞疗法可持久缓解艾滋病毒。
英文摘要
Project Summary
MarPam Pharma aims to develop a one-time treatment for achieving durable remission of human
immunodeficiency virus (HIV), after which patients will no longer need to take antiretroviral therapy. Our
treatment is an autologous HIV-specific chimeric antigen receptor (CAR) immune cell therapy that employs the
CXCR5 chemokine receptor as a homing device to direct either anti-HIV T cells or anti-HIV natural killer (NK)
cells into immune-protected “hidden” viral reservoirs in lymphoid B cell follicles, where most virus-producing cells
are located during chronic infection. Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and
Simian immunodeficiency virus (SIV), an animal model of HIV. Nevertheless, despite abundant CD8 T cell
responses in HIV-1-infected humans and SIV-infected macaques, these cells do not fully suppress virus
replication, likely because the majority of HIV-1 and SIV replication occurs in CD4+ T cells concentrated within
B cell follicles in secondary lymphoid tissues, where surprisingly few virus-specific CD8 T cells reside in infected
individuals. In fact, we found 40-fold lower levels of in vivo effector CTL to target viral (v)RNA+ cells (E:T) inside
compared to outside of B cell follicles, likely explained by the fact that very few virus-specific CD8 T cells express
the follicular homing molecule CXCR5. These findings suggest that the inability of HIV-specific CD8 T cells to
fully suppress virus replication may be due to a deficiency of virus-specific CD8 T cells in B cell follicles. As the
vast majority of virus-producing cells are CD4 T cells located in secondary lymphoid tissue and concentrated in
follicles during chronic HIV and SIV infections, we targeted these infected cells by infusing autologous antiviral
CAR/CXCR5-T cells in chronically SIV-infected rhesus macaques. The treated animals showed successful
homing of CAR/CXCR5-T cells to B cell follicles, evidence of direct contact of the CAR/CXCR5-T cells with
vRNA+ infected cells and decreased viral loads in treated animals compared to untreated animals. Our pilot
study showed that the treatment was safe and effective. These findings have prompted us to further refine
our promising targeted CAR/CXCR5-T cell therapy by enhancing its efficacy and to investigate whether this
targeted immune cell therapy could be developed using NK cells. CAR-T and CAR-NK cell therapies are
individualized therapies that modify a patient’s own immune cells to fight disease; NK cell therapies also have
the potential to function as off-the-shelf treatments using allogenic cells. This proposal seeks to optimize the
effectiveness of our CAR/CXCR5 immune cell therapy. In addition, we aim to generate and evaluate optimized
Car/CXCR5-T and -NK cells using less expensive production methods. Successful completion of the proposed
studies will lead to Phase II IND-enabling primate studies to assess the safety and efficacy of the T cell and NK
cell therapies for durable HIV remission.
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A novel CAR-T cell therapy for the one-time treatment of chronic HIV infection in patients who are not ART suppressed
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批准号:10739333
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项目类别:
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资助金额:$5.5万
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财政年份:2023
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负责人:Maria Constance Athanasiou
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依托单位:
A novel CAR-T cell therapy for the one-time treatment of chronic HIV infection in patients who are not ART suppressed
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批准号:10547203
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项目类别:
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资助金额:$30.0万
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财政年份:2022
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负责人:Maria Constance Athanasiou
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依托单位:
Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles
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批准号:10080592
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项目类别:
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资助金额:$30.0万
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财政年份:2020
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负责人:Maria Constance Athanasiou
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依托单位:
Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles
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批准号:10348815
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项目类别:
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资助金额:$5.2万
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财政年份:2020
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负责人:Maria Constance Athanasiou
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依托单位:
Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles
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批准号:10738349
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项目类别:
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资助金额:$11.85万
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财政年份:2020
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负责人:Maria Constance Athanasiou
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依托单位:
Development of a treatment for the durable remission of HIV using autologous human CAR T cells that target B cell follicles
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批准号:10326301
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项目类别:
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资助金额:$101.9万
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财政年份:2020
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负责人:Maria Constance Athanasiou
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依托单位:
海外基金