Project 4: Chimeric Antigen Receptor T Cell Therapy for the Treatment of Acute Myeloid Leukemia
Project 4: Chimeric Antigen Receptor T Cell Therapy for the Treatment of Acute Myeloid Leukemia
批准号:
10474300
负责人:
Renier Joseph Brentjens
金额:
$36.77万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-24 至 2026-06-30
关键词:
Acute Myelocytic LeukemiaAcute leukemiaAddressAdultAftercareAntigen TargetingAntigensAntitumor ResponseCAR T cell therapyCD19 geneCell surfaceCharacteristicsChemoresistanceClinicalClinical TreatmentCorrelative StudyDevelopmentDiseaseDisease MarkerDisease remissionGoalsHematopoiesisHematopoietic stem cellsHumanImmuneImmune TargetingImmune responseImmunophenotypingIncidenceInterleukin-18Investigational TherapiesLarge-Cell LymphomasMaximum Tolerated DoseMediatingMemorial Sloan-Kettering Cancer CenterMinorityMyeloid CellsMyeloid LeukemiaNatural regenerationOutcomePathologicPatientsPhase I Clinical TrialsRecurrent diseaseRefractoryRegimenRelapseRemission InductionSafetySecondary toSurvival RateT cell responseT-LymphocyteTestingTherapeuticToxic effectTransplantationTreatment outcomeTumor-infiltrating immune cellsVaccinationVariantVertebral columnacute myeloid leukemia cellanti-tumor immune responsebasecancer cellchemotherapychimeric antigen receptor T cellscytokineimmune clearanceimmunogenicityimprovedleukemialeukemia/lymphomaleukemic stem cellneoplastic cellnovelpatient derived xenograft modelpre-clinicalreconstitutionresponseresponse biomarkertherapy developmenttumortumor microenvironment
中文摘要
摘要
英文摘要
ABSTRACT
There is an urgent and critical need for the development of leukemia stem cell (LSC)-directed therapeutic
approaches for the treatment of acute myeloid leukemia (AML). One such strategy is targeting antigens that
are specific to LSCs but absent from normal hematopoietic stem cells (HSCs). CD371 (CLEC12A, CLL-1),
which is present on mature myeloid cells, has been described as one such targetable disease marker given its
presence on both bulk AML cells and LSCs. Although not ubiquitously expressed on all AML cells, it is
expressed in up to 95% of AML patients, is enriched on LSCs and chemoresistant AML subpopulations, and
most importantly, is absent on HSCs.
We have successfully developed and validated a fully-human CD371-targeted chimeric antigen receptor (CAR)
T cell product which also secretes IL-18. Given that our CD371-targeting motif is entirely human, it is expected
to have reduced immunogenicity and thus minimizes host-mediated CAR T cell-directed immune elimination in
the context of constitutive IL18 secretion. In addition, IL18 secretion is predicted to enhance CAR T cell
persistence and modulation the tumor microenvironment (TME) by increasing and activating immune cell
infiltrates, leading to the induction of an endogenous T cell mediated anti-tumor immune-response capable of
eradicating antigen-negative tumor cell subpopulations.
Our central hypothesis is that CD371-targeted IL18-secreting CAR T cells will lead to eradication of antigen-
positive chemoresistant and LSC subpopulations, and the induction of an endogenous AML-reactive T cell
response that will lead to elimination of antigen-negative disease, without long-term HSC toxicity. This will be
tested in AML patient-derived xenograft models of heterogeneously antigen-positive disease (Aim 1) and a
phase I clinical trial with CD371-targeted IL18-secreting CAR T cells in patients with relapsed/refractory AML
(Aim 2). This effort will therefore assess the safety and efficacy of this novel CAR-T cell approach in both
preclinical and clinical settings, and will also address biomarkers of response and efficacy in numerous
correlative studies (Aim 3).
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Optimizing Dual-Targeted and Dual-Armored CAR T Cells for Small Cell LungCancer
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批准号:10380107
-
项目类别:
-
资助金额:$63.07万
-
财政年份:2021
-
负责人:Renier Joseph Brentjens
-
依托单位:
Optimizing Dual-Targeted and Dual-Armored CAR T Cells for Small Cell LungCancer
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批准号:10523835
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项目类别:
-
资助金额:$58.5万
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财政年份:2021
-
负责人:Renier Joseph Brentjens
-
依托单位:
MSK Paul Calabresi Career Development Award for Clinical Oncology
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批准号:8875305
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项目类别:
-
资助金额:$5.4万
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财政年份:2015
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负责人:Renier Joseph Brentjens
-
依托单位:
MSK Paul Calabresi Career Development Award for Clinical Oncology
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批准号:9788288
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项目类别:
-
资助金额:$80.8万
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财政年份:2015
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负责人:Renier Joseph Brentjens
-
依托单位:
Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
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批准号:8143046
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项目类别:
-
资助金额:$195.15万
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财政年份:2010
-
负责人:Renier Joseph Brentjens
-
依托单位:
Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
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批准号:8019552
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项目类别:
-
资助金额:$38.16万
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财政年份:2009
-
负责人:Renier Joseph Brentjens
-
依托单位:
Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
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批准号:8214708
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项目类别:
-
资助金额:$38.16万
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财政年份:2009
-
负责人:Renier Joseph Brentjens
-
依托单位:
Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
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批准号:8444267
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项目类别:
-
资助金额:$35.87万
-
财政年份:2009
-
负责人:Renier Joseph Brentjens
-
依托单位:
Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
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批准号:7634005
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项目类别:
-
资助金额:$39.34万
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财政年份:2009
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负责人:Renier Joseph Brentjens
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依托单位:
Genetic Targeting of T cells to B cell malignancies
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批准号:6951500
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项目类别:
-
资助金额:$13.44万
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财政年份:2003
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负责人:Renier Joseph Brentjens
-
依托单位:
Genetic Targeting of T cells to B cell malignancies
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批准号:6785519
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项目类别:
-
资助金额:$13.44万
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财政年份:2003
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负责人:Renier Joseph Brentjens
-
依托单位:
Genetic Targeting of T cells to B cell malignancies
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批准号:6687407
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项目类别:
-
资助金额:$13.42万
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财政年份:2003
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负责人:Renier Joseph Brentjens
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依托单位:
Autologous CD19 Targeted 19-28z+ Tcells for the Treatment of Relapsed Diffuse Large B cell Lymphoma in Transplant Ineligible Elderly Patients
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批准号:9754071
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项目类别:
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资助金额:$30.45万
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财政年份:--
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负责人:Renier Joseph Brentjens
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依托单位:
Autologous CD19 Targeted 19-28z+ Tcells for the Treatment of Relapsed Diffuse Large B cell Lymphoma in Transplant Ineligible Elderly Patients
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批准号:9565736
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项目类别:
-
资助金额:$32.59万
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财政年份:--
-
负责人:Renier Joseph Brentjens
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依托单位:
海外基金