Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute lymphoblastic leukemia
项目 4:现成的工程化脐带血自然杀伤细胞,用于治疗急性淋巴细胞白血病
基本信息
- 批准号:10931069
- 负责人:
- 金额:$ 29.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAdoptive Cell TransfersAdoptive TransferAdultAdvanced Malignant NeoplasmAdvisory CommitteesAllogenicAntigen TargetingAntigensAutologousB lymphoid malignancyB-LymphocytesBlood BanksCAR T cell therapyCASP9 geneCD19 geneCD3 AntigensCancer CenterCancer PatientCell TherapyCell physiologyCellsClinicClinicalClinical ProtocolsClinical ResearchClinical TrialsCorrelative StudyDataDisadvantagedDiseaseDoctor of MedicineDominant GenesDominant-Negative MutationDoseEffector CellEngineeringEquipment and supply inventoriesExhibitsFreezingGenerationsGenetic EngineeringHumanIn VitroIndividualInnate Immune SystemInstitutional Review BoardsInterleukin-15LaboratoriesLeukapheresisLymphoidMalignant NeoplasmsMeasuresMediatingMethodsModalityMusNatural Killer Cell toxicityNatural Killer CellsPatient-Focused OutcomesPatientsPositioning AttributeProliferatingProtocols documentationRecombinant DNARefractoryRegulationRelapseReportingReproducibilityResearchRetroviral VectorRiskRisk ReductionSafetySamplingSeriesSignal TransductionSourceSpecificityT-Cell ReceptorT-LymphocyteTestingTexasTherapeuticToxic effectTransforming Growth Factor betaUmbilical Cord BloodUniversitiesacute lymphoblastic leukemia celladvanced diseasealpha-beta T-Cell Receptorantileukemic activitycancer cellcancer therapycellular transductionchimeric antigen receptorchimeric antigen receptor T cellschimeric geneclinically relevantconventional therapycost effectivecytokinecytokine release syndromecytotoxicityengineered NK cellfirst-in-humangraft vs host diseaseimmunoengineeringimmunotherapy clinical trialsimproved outcomein vivoindividual patientinnovationleukemiamanufacturenext generationnovelnovel strategiespharmacologicpre-clinicalpreclinical studyreceptorreconstitutionrefractory cancerrelapse riskresponsesafety testingscreeningsuicide genetumortumor-immune system interactionsvector
项目摘要
Summary:
The past several years have seen tremendous advances in the engineering of immune effector cells as
therapy for cancer. However, chimeric antigen receptor (CAR)-modified T-cells have a number of limitations.
The generation of an autologous product for each individual patient is logistically cumbersome and restrictive
for widespread clinical use. The manufacturing of CAR T-cells often takes several weeks, making it impractical
for patients with rapidly advancing disease. Furthermore, it is not always possible to generate clinically relevant
doses of CAR T-cells from heavily pre-treated, often lymphopenic patients. A previously collected allogeneic
product could overcome these limitations; however, allogeneic T-cells (even if HLA-matched) carry a
significant risk of graft-versus-host disease (GVHD) mediated through their native αβ T-cell receptor prohibiting
their use as a clinical product without further manipulation to eliminate the T cell receptor. Natural killer (NK)
cells provide an extremely attractive alternative to T-cells for CAR engineering. NK cells do not cause GVHD
and thus open opportunities to produce an off-the-shelf product for immediate clinical use. Moreover, as
engineered NK cells should also retain their full array of native receptors, they have the potential to exert
cytotoxicity through mechanisms other than that dictated by the specificity of the CAR, which in principle could
reduce the risk of relapse mediated by loss of CAR-targeted antigen, as reported for CAR-T cell therapy.
Autologous NK cells can be reproducibly generated in vitro, but have extremely limited activity against
autologous tumor which cannot be overcome by CAR engineering. Cord blood (CB) is a readily available
source of allogeneic NK cells with clear advantages. CB is available as an off-the-shelf frozen product, an
advantage that has been bolstered by methods to generate large numbers of highly functional NK cells from
frozen CB units ex vivo. The generation of CAR-transduced NK cells from frozen CB units stored in large
global CB bank inventories holds promise for widespread scalability that cannot be replicated with individual
adult donors who require screening and leukapheresis.
In Aim 1 we will perform the first-inhuman clinical trial to test the safety and efficacy of CB-NK cells engineered
to express a CAR against CD19 (a B cell-specific antigen), to ectopically produce IL-15 to support their in vivo
proliferation and persistence, and to express a suicide gene, based on IC9, that will address safety concerns
related to the potential risk of direct toxicity; In Aim 2 we will apply highly innovative correlative studies to
describe the therapeutic potential of the clinical trial; Aim 3 in preclinical murine studies, we will protect the
transduced NK cells from the TGF-β/SMAD signaling axis using a novel retroviral construct that, in addition to
CAR.CD19 and IL-15, includes the gene for the dominant-negative version of human TGFβ receptor II (TGFβ-
DNRII) for next-generation clinical studies.
简介:
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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Katy Rezvani其他文献
Katy Rezvani的其他文献
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{{ truncateString('Katy Rezvani', 18)}}的其他基金
Next-Generation Engineered NK Cell Immunotherapy for Ovarian Cancer
下一代卵巢癌工程 NK 细胞免疫疗法
- 批准号:
10709230 - 财政年份:2023
- 资助金额:
$ 29.34万 - 项目类别:
Off-the-shelf engineered NK cells for the treatment of AML
用于治疗 AML 的现成工程 NK 细胞
- 批准号:
10162818 - 财政年份:2020
- 资助金额:
$ 29.34万 - 项目类别:
Off-the-shelf engineered NK cells for the treatment of AML
用于治疗 AML 的现成工程 NK 细胞
- 批准号:
9210330 - 财政年份:2016
- 资助金额:
$ 29.34万 - 项目类别:
CMV infection and NK-cell therapy for multiple myeloma
CMV 感染和 NK 细胞治疗多发性骨髓瘤
- 批准号:
9178822 - 财政年份:2016
- 资助金额:
$ 29.34万 - 项目类别:
Off-the-shelf engineered NK cells for the treatment of AML
用于治疗 AML 的现成工程 NK 细胞
- 批准号:
10058761 - 财政年份:2016
- 资助金额:
$ 29.34万 - 项目类别:
Off-the-Shelf Engineered Cord Blood NK Cells for the Treatment of Hematologic Malignancies.
用于治疗血液恶性肿瘤的现成工程脐带血 NK 细胞。
- 批准号:
10247039 - 财政年份:2011
- 资助金额:
$ 29.34万 - 项目类别:
Off-the-Shelf Engineered Cord Blood NK Cells for the Treatment of Hematologic Malignancies.
用于治疗血液恶性肿瘤的现成工程脐带血 NK 细胞。
- 批准号:
10478148 - 财政年份:2011
- 资助金额:
$ 29.34万 - 项目类别:
Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute lymphoblastic leukemia
项目 4:现成的工程化脐带血自然杀伤细胞,用于治疗急性淋巴细胞白血病
- 批准号:
10006816 - 财政年份:2003
- 资助金额:
$ 29.34万 - 项目类别:
Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute lymphoblastic leukemia
项目 4:现成的工程化脐带血自然杀伤细胞,用于治疗急性淋巴细胞白血病
- 批准号:
10247506 - 财政年份:2003
- 资助金额:
$ 29.34万 - 项目类别: