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
因此,迫切需要开发白血病干细胞(LSC)靶向治疗药物。
治疗急性髓细胞白血病(AML)的方法。一种这样的策略是靶向抗原,
对LSC是特异性的,但不存在于正常造血干细胞(HSC)中。CD371(CLEC12A,CLL-1),
存在于成熟的骨髓细胞上,已经被描述为一种这样的可靶向的疾病标志物,
存在于大量AML细胞和LSC上。虽然不是在所有AML细胞上普遍表达,但它是
在高达95%的AML患者中表达,在LSC和化疗耐药AML亚群上富集,
最重要的是,它在HSC上不存在。
我们已经成功开发并验证了一种完全人CD 371靶向的嵌合抗原受体(CAR),
也分泌IL-18的T细胞产物。考虑到我们的CD 371靶向基序完全是人类的,
具有降低的免疫原性,从而使宿主介导的CAR T细胞介导的免疫消除最小化,
组成型IL 18分泌的背景。此外,预计IL 18分泌可增强CAR T细胞
通过增加和激活免疫细胞来维持和调节肿瘤微环境(TME)
浸润,导致诱导内源性T细胞介导的抗肿瘤免疫应答,
根除抗原阴性肿瘤细胞亚群。
我们的中心假设是,CD 371靶向的分泌IL 18的CAR T细胞将导致抗原的根除。
阳性化疗耐药和LSC亚群,以及诱导内源性AML反应性T细胞
这将导致抗原阴性疾病的消除,而没有长期的HSC毒性。这将是
在异源性抗原阳性疾病的AML患者来源的异种移植物模型(Aim 1)和
在复发性/难治性AML患者中使用CD 371靶向IL 18分泌CAR T细胞的I期临床试验
(Aim 2)。因此,这项工作将评估这种新型CAR-T细胞方法在两种疾病中的安全性和有效性。
临床前和临床环境,并将解决生物标志物的反应和疗效,在许多
相关研究(目标3)。
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
-
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
-
批准号:10523835
-
项目类别:
-
资助金额:$58.5万
-
财政年份:2021
-
负责人:Renier Joseph Brentjens
-
依托单位:
MSK Paul Calabresi Career Development Award for Clinical Oncology
-
批准号:8875305
-
项目类别:
-
资助金额:$5.4万
-
财政年份:2015
-
负责人:Renier Joseph Brentjens
-
依托单位:
MSK Paul Calabresi Career Development Award for Clinical Oncology
-
批准号:9788288
-
项目类别:
-
资助金额:$80.8万
-
财政年份:2015
-
负责人:Renier Joseph Brentjens
-
依托单位:
Adoptive Immunotherapy of Cancer with IL-12 Secreting Tumor-Targeted T cells
-
批准号:8143046
-
项目类别:
-
资助金额:$195.15万
-
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
-
批准号:8019552
-
项目类别:
-
资助金额:$38.16万
-
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
-
批准号:8214708
-
项目类别:
-
资助金额:$38.16万
-
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
-
批准号:8444267
-
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
-
批准号:7634005
-
项目类别:
-
资助金额:$39.34万
-
财政年份:2009
-
负责人:Renier Joseph Brentjens
-
依托单位:
Genetic Targeting of T cells to B cell malignancies
-
批准号:6951500
-
项目类别:
-
资助金额:$13.44万
-
财政年份:2003
-
负责人:Renier Joseph Brentjens
-
依托单位:
Genetic Targeting of T cells to B cell malignancies
-
批准号:6785519
-
项目类别:
-
资助金额:$13.44万
-
财政年份:2003
-
负责人:Renier Joseph Brentjens
-
依托单位:
Genetic Targeting of T cells to B cell malignancies
-
批准号:6687407
-
项目类别:
-
资助金额:$13.42万
-
财政年份:2003
-
负责人:Renier Joseph Brentjens
-
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
-
项目类别:
-
资助金额:$30.45万
-
财政年份:--
-
负责人:Renier Joseph Brentjens
-
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
-
批准号:9565736
-
项目类别:
-
资助金额:$32.59万
-
财政年份:--
-
负责人:Renier Joseph Brentjens
-
依托单位:
海外基金