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Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: Beyond CART 19

Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: Beyond CART 19
增强嵌合抗原受体 T 细胞治疗血液恶性肿瘤:超越 CART 19
批准号:
10713199
负责人:
CARL H. JUNE
金额:
$278.23万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
未结题
起止时间:
2017-08-15 至 2028-08-31
关键词:
Acute Myelocytic LeukemiaAcute T Cell LeukemiaAcute leukemiaAddressAdoptive TransferAuthorization documentationAutoimmune DiseasesB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaBackBiologicalBiometryBloodCAR T cell therapyCD19 geneCRISPR/Cas technologyCTLA4 geneCell TherapyCellsChronic Lymphocytic LeukemiaClinicClinicalClinical TrialsCollaborationsDevelopmentDisciplineDiseaseEngineeringFDA approvedFundingFutureGenerationsGenesGeneticGenetic EngineeringGillsGoalsHematologic NeoplasmsHematopoiesisHematopoietic NeoplasmsHematopoietic SystemHuman GenomeImmuneImmunologicsImmunotherapyIn complete remissionIndividualInterleukin-2InternationalJointsJournalsLaboratoriesLicensingLymphoblastic LeukemiaLymphomaMalignant NeoplasmsMarrowMediatingMedicalMedicineMessenger RNAModificationMonitorMultiple MyelomaMutateMyeloid LeukemiaNew EnglandPTPRC genePaperPatientsPersonsPublicationsPublishingRefractoryRelapseResearchResearch PersonnelResistanceResource SharingSafetySamplingServicesSmall-Cell LymphomaSolidSourceSurface AntigensT-LymphocyteTechnologyTestingTherapeuticToxic effectTranslatingUnited StatesVaccinesantitumor effectauthoritybase editingbench to bedsidecancer cellcancer immunobiologycancer immunotherapychimeric antigen receptorchimeric antigen receptor T cellsclinical investigationefficacy testingengineered T cellsgene therapygenome editingimprovedindexinginnovationleukemialeukemia/lymphomalipid nanoparticlemanufacturing facilitymultidimensional datanext generationnovelnovel therapeuticsoverexpressionpreclinical studyprogramsrational designstandard of caresynthetic biologytooltumor

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中文摘要
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整体项目摘要/摘要
英文摘要
OVERALL PROJECT SUMMARY / ABSTRACT The long-term goals of this renewal P01 are to develop next generation immunotherapy with chimeric antigen receptor (CAR) T cells and to translate this research into new therapies with curative potential for patients with blood cancer. The CAR developed at our center was the first cell and gene therapy to ever receive approval from the FDA, initially for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL) in 2017 and lymphoma in 2018. However, multiple myeloma (MM), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies with combination of CAR T cells and advanced forms of human genome editing will enable this powerful therapy to reach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptional investigators from multiple disciplines who have collaborated and published together for many years. Each disease-focused project will be led by recognized authorities in the field. To achieve our goals, we have three Projects that build on progress during the previous funding period and will continue to coordinate closely with essential shared resource cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) CAR T cells targeting CD19 will be tested with genetic disruption of CD5, CTLA- 4 and TET2 to address CLL and lymphoma, which is lack of sustained effector CAR T function in these patients. In AML, the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AML but lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window for AML by genetically-modifying normal marrow to make it resistant to killing by anti-AML CAR T cells, and delivering potent anti-leukemic CAR T cells specific for CD45. Engineered HSC that are genetically edited to install a hematopoietic system facilitating non-toxic therapy with these potent CAR T cells will be developed. In Project 3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) testing the efficacy of marrow- derived CAR T compared to current standard of care blood-derived CAR T (ii) improving persistence of BCMA CAR T with orthogonally mutated IL-2/IL-2R technology and mRNA/lipid-nanoparticle vaccine technology to overcome suboptimal persistence and efficacy of current BCMA T cells. The Scientific and Administrative Cores for this P01 are essential for our progress including provision of project management for collaboration and biostatistics, clinical safety and monitoring, and fiscal support (Core A), a GMP facility for manufacture of cells and identification of new binders for CAR targets (Core B), and a state-of- the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (Core C). Our renewal application has the potential for paradigm-shifting impact to transform the lessons of CAR T for ALL into meaningful efficacy against all hematologic malignancies, solid cancers and provides direction for extending beyond cancer to autoimmune disorders.
期刊论文(72)
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会议论文
DOI: 10.1182/bloodadvances.2021005304
发表时间: 2021-10-26
期刊: Blood advances
影响因子: 7.5
作者: [Ho C, Ruella M, Levine BL, Svoboda J]
通讯作者: Svoboda J
DOI: 10.1056/nejmra1706169
发表时间: 2018-07-05
期刊: The New England journal of medicine
影响因子: --
作者: [June CH, Sadelain M]
通讯作者: Sadelain M
DOI: 10.1200/jco.19.01892
发表时间: 2020-02-10
期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子: --
作者: [Frey NV, Shaw PA, Hexner EO, Pequignot E, Gill S, Luger SM, Mangan JK, Loren AW, Perl AE, Maude SL, Grupp SA, Shah NN, Gilmore J, Lacey SF, Melenhorst JJ, Levine BL, June CH, Porter DL]
通讯作者: Porter DL
DOI: 10.1016/j.xkme.2021.03.011
发表时间: 2021-07
期刊: Kidney medicine
影响因子: 3.9
作者: [Melilli E, Mussetti A, Linares GS, Ruella M, La Salette C, Savchenko A, Taco MDR, Montero N, Grinyo J, Fava A, Gomà M, Meneghini M, Manonelles A, Cruzado J, Sureda A, Bestard O]
通讯作者: Bestard O
38
    Engineering the Next Generation of T Cells
    • 批准号:
      10578324
    • 项目类别:
    • 资助金额:
      $24.38万
    • 财政年份:
      2019
    • 负责人:
      CARL H. JUNE
    • 依托单位:
    Engineering the next generation of T cells
    • 批准号:
      10064451
    • 项目类别:
    • 资助金额:
      $23.31万
    • 财政年份:
      2019
    • 负责人:
      CARL H. JUNE
    • 依托单位:
    Directing the metabolic fate of CAR T cells
    • 批准号:
      10364746
    • 项目类别:
    • 资助金额:
      $42.37万
    • 财政年份:
      2018
    • 负责人:
      CARL H. JUNE
    • 依托单位:
    Project 2: Towards a safe and effective AML treatment strategy using anti-CD33 CAR T cells in combination with CAR-resistant hematopoietic stem cells
    • 批准号:
      10245064
    • 项目类别:
    • 资助金额:
      $31.74万
    • 财政年份:
      2017
    • 负责人:
      CARL H. JUNE
    • 依托单位:
    海外基金