Development of Allogeneic CAR T Cell Therapy for a Functional Cure of HIV Infection
开发同种异体 CAR T 细胞疗法以功能性治愈 HIV 感染
基本信息
- 批准号:10581704
- 负责人:
- 金额:$ 47.16万
- 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
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAllogenicAnti-Retroviral AgentsAutologousB-Cell Acute Lymphoblastic LeukemiaBerlinBindingCAR T cell therapyCCR5 geneCD19 geneCD28 geneCD8-Positive T-LymphocytesCardiovascular DiseasesCellsCellular biologyCellular immunotherapyCharacteristicsChronicClinicalClinical TrialsConsumptionCytomegalovirusDNADataDevelopmentDiseaseDisease ProgressionDisease remissionExhibitsFunctional disorderGenerationsGenesGeneticHIVHIV InfectionsHIV vaccineHeadHematopoietic NeoplasmsHeterogeneityHumanImmuneImmune responseImmune systemImmunotherapeutic agentImmunotherapyIndividualInfectionInflammationInfusion proceduresInterruptionJunk DNAKnowledgeLondonMacaca mulattaMalignant NeoplasmsMediatingModificationMorbidity - disease ratePathogenesisPathogenicityPatientsPharmaceutical PreparationsPhenotypeProductionResistanceSIVSourceT cell responseT-Cell DevelopmentT-LymphocyteTestingTherapeuticTimeTissuesVaccinationVariantViralViral Load resultViral reservoirVirusallotransplantanti-viral efficacyantiretroviral therapybase editingcancer immunotherapychimeric antigen receptorchimeric antigen receptor T cellschronic infectioncostefficacy studyengineered T cellshuman diseasehumanized mouseimprovedin vivointerestmanufacturing costmortalitymouse modelnovelpreventprophylacticresponsestem cellssuccesstranscriptomicstumorvector inducedvector-based vaccineviral rebound
项目摘要
Abstract: Antiretroviral therapy (ART) dramatically reduces HIV-associated morbidity and mortality (1).
However, it is not a practical cure as eradication of HIV through ART alone is estimated to require over 60 years
of treatment (1, 2). Numerous studies support that HIV-specific T cell responses are critical for efficient targeting
and elimination of HIV infected cells that are the source of chronic infection (3-10). Unfortunately, viral escape
and a limited presence of functional virus-specific effector CD8+ T cells undermine the potency of these
responses in chronically infected individuals (11-17). As such, there is growing interest in the development of
novel immunotherapeutic approaches to target and eliminate HIV-infected cells to achieve viral
suppression in the absence of ART, a “functional cure”.
Chimeric antigen receptor (CAR) T cell immunotherapies have demonstrated great promise against
blood cancers (18-20), and now also demonstrate the potential to mitigate HIV/SIV infection in rhesus macaques
(21, 22) and humanized mice (23-28). We recently showed that HIV-specific Dual CD4-based CAR T cells co-
expressing independent 4-1BB and CD28 costimulatory domains restrict HIV replication and reduce viral burden
in humanized mice (23). However, current limitations of using autologous T cells to derive CAR T cell products
(TCPs), including time-consuming and costly manufacturing, insufficient or dysfunctional patient-derived T cells,
and the inter-patient heterogeneity of TCPs, are barriers to their widespread application to human diseases.
Development of allogeneic TCPs derived from healthy human donors, could, however, provide an ‘off-the-shelf’
treatment option to overcome these hurdles, as well as accelerate the use of CAR T cell therapies (29-38).
Unfortunately, post-infusion elimination by the recipient’s immune system remains a major hurdle (39-41).
Here we propose to leverage our expertise in CAR T cell biology (21, 23, 25, 26, 42, 43), base editing
(44-49), and a humanized mouse model of HIV infection (50-58) to develop an allogeneic CAR T cell therapy
against HIV. Building on our preliminary data applying efficient multiplex base editing to CAR T cells, we
hypothesize that both base editing approaches and identification of an optimal allogenic donor will enable the
development of an allorejection-resistant CD4-based CAR TCP with enhanced efficacy to eliminate HIV-infected
cells and suppress HIV in the absence of ART. To test this hypothesis, we propose the following specific aims:
Aim 1: Determine whether genetic modifications to allogeneic T cells can augment their in vivo
persistence.
Aim 2: Identify characteristics of allogeneic HIV-specific CD4CAR T cells that associate with enhanced
persistence and antiviral efficacy.
Aim 3: Compare the in vivo HIV efficacy of allogeneic versus autologous HIV-specific CD4CAR T cells,
incorporating Aim 1 and 2’s signatures of improved allogeneic functionality.
摘要:抗逆转录病毒治疗(ART)显着降低了艾滋病毒相关的发病率和死亡率(1)。
然而,这不是一种实际的治疗方法,因为仅通过抗逆转录病毒疗法根除艾滋病毒估计需要60多年的时间。
治疗(1,2)。大量研究支持HIV特异性T细胞应答对于有效靶向至关重要
以及清除作为慢性感染源的HIV感染细胞(3 - 10)。不幸的是,病毒逃逸
并且功能性病毒特异性效应CD8 + T细胞的有限存在破坏了这些细胞的效力。
慢性感染者的反应(11 - 17)。因此,人们对开发
靶向和消除HIV感染细胞以实现病毒免疫的新方法
在没有ART的情况下进行抑制,这是一种“功能性治愈”。
嵌合抗原受体(CAR)T细胞免疫疗法已经显示出巨大的前景,
血癌(18 - 20),现在也证明了在恒河猴中减轻HIV/SIV感染的潜力
(21,22)和人源化小鼠(23 - 28)。我们最近发现,HIV特异性的基于CD4的双重CAR T细胞共表达,
表达独立的4 - 1BB和CD28共刺激结构域限制HIV复制并降低病毒负荷
在人源化小鼠中(23)。然而,目前使用自体T细胞来衍生CAR T细胞产物的局限性在于,
(TCP),包括耗时和昂贵的制造,患者来源的T细胞不足或功能障碍,
和患者间TCP的异质性是其广泛应用于人类疾病的障碍。
然而,开发来自健康人类供体的同种异体TCP可以提供一种"现成的"
克服这些障碍的治疗选择,以及加速CAR T细胞疗法的使用(29 - 38)。
不幸的是,接受者免疫系统的输注后消除仍然是一个主要障碍(39 - 41)。
在这里,我们建议利用我们在CAR T细胞生物学(21,23,25,26,42,43),碱基编辑,
(44 - 49)和HIV感染的人源化小鼠模型(50 - 58)以开发同种异体CAR T细胞疗法。
对抗艾滋病病毒。基于我们将有效的多重碱基编辑应用于CAR T细胞的初步数据,我们
假设碱基编辑方法和最佳同种异体供体鉴定都将使
开发一种具有增强疗效的抗同种异体排斥的基于CD4的CAR TCP,以消除HIV感染者。
为了验证这一假设,我们提出了以下具体目标:
目的1:确定对同种异体T细胞的遗传修饰是否可以增加其在体内的表达。
坚持不懈
目的2:鉴定与增强的免疫应答相关的同种异体HIV特异性CD4CAR T细胞的特征。
持久性和抗病毒功效。
目的3:比较同种异体与自体HIV特异性CD4CAR T细胞的体内HIV功效,
结合Aim 1和Aim 2的改善同种异体功能的特征。
项目成果
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TODD M ALLEN其他文献
TODD M ALLEN的其他文献
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{{ truncateString('TODD M ALLEN', 18)}}的其他基金
Development of Allogeneic CAR T Cell Therapy for a Functional Cure of HIV Infection
开发同种异体 CAR T 细胞疗法以功能性治愈 HIV 感染
- 批准号:
10480991 - 财政年份:2022
- 资助金额:
$ 47.16万 - 项目类别:
Next-Generation Sequencing Center for GHOSTing Hepatitis C Virus: Transforming Community Based Molecular Surveillance and Outbreak Investigation
丙型肝炎病毒重影的下一代测序中心:改变基于社区的分子监测和疫情调查
- 批准号:
10241239 - 财政年份:2017
- 资助金额:
$ 47.16万 - 项目类别:
Leveraging Genetic Engineering Towards a Functional Cure of HIV Infection
利用基因工程实现艾滋病毒感染的功能性治愈
- 批准号:
8897540 - 财政年份:2015
- 资助金额:
$ 47.16万 - 项目类别:
Optimizing Human B and T Cell Vaccines Against HIV Using Humanized BLT Mice
使用人源化 BLT 小鼠优化针对 HIV 的人类 B 和 T 细胞疫苗
- 批准号:
8994707 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
Optimizing CD8+ T Cell Vaccine Responses Against HIV
优化 CD8 T 细胞疫苗对 HIV 的反应
- 批准号:
8492547 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
Optimizing Human B and T Cell Vaccines Against HIV Using Humanized BLT Mice
使用人源化 BLT 小鼠优化针对 HIV 的人类 B 和 T 细胞疫苗
- 批准号:
8487593 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
Optimizing Human B and T Cell Vaccines Against HIV Using Humanized BLT Mice
使用人源化 BLT 小鼠优化针对 HIV 的人类 B 和 T 细胞疫苗
- 批准号:
8788494 - 财政年份:2013
- 资助金额:
$ 47.16万 - 项目类别:
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