Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
批准号:
10305133
负责人:
Hideho Okada
金额:
$29.09万
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:
2021-09-10 至 2026-08-31
关键词:
AdolescentAdoptedAdultAntigensB lymphoid malignancyBiodistributionBloodBrainBrain NeoplasmsCell TherapyCellsClinicalClinical TrialsDataDevelopmentDoseEngraftmentEnrollmentEpidermal Growth Factor ReceptorFundingGlioblastomaGoalsGrantHeterogeneityHomingHumanImmunologic MonitoringImmunotherapyIn VitroInfiltrationInflammationInstitutesIntravenousIntravenous infusion proceduresInvestigational DrugsInvestigational New Drug ApplicationLentivirusLentivirus VectorMalignant NeoplasmsMaximum Tolerated DoseMedicalMemoryMethodsNeuraxisNew Drug ApprovalsOperative Surgical ProceduresOrganPatientsPharmacodynamicsPhasePhase I Clinical TrialsPhenotypePre-Clinical ModelProceduresProcessRecurrenceResearch PersonnelResectedSafetySignal TransductionSolidSurface AntigensSystemT cell therapyT-LymphocyteTestingTimeTissuesToxic effectToxicologyTumor TissueUltrasonographyUnited States National Institutes of Healthbaseblood-brain tumor barrierbody systemcancer immunotherapychimeric antigen receptorchimeric antigen receptor T cellscohortcytotoxicitydesignepidermal growth factor receptor VIIIexhaustionexperiencefirst-in-humanin vivoinnovationmanufacturing processmutantneoplasm immunotherapyneoplastic cellnotch proteinnovelpatient derived xenograft modelphase 1 studyphase I trialpreclinical efficacyprospectivequality assurancereceptorstemtumor
中文摘要
开发安全有效的(CAR)转导T细胞(CART)治疗胶质母细胞瘤(GBM)需要
克服多重挑战,包括靶向肿瘤外毒性、抗原表达的异质性,以及
耗尽CART细胞。在肿瘤中没有均匀存在的GBM特异性表面抗原,
组织.例如,突变型表皮生长因子受体(EGFRvIII)是GBM特异性的,但其表达是特异性的。
在肿瘤内是异质的。另一方面,虽然非突变的GBM相关抗原(GAA),如
如EphA 2和IL-13 R α2,在GBM中更均匀地表达,它们在GBM外的其他器官中的表达,
中枢神经系统(CNS)引起了对肿瘤外毒性的关注。作为一种安全有效地瞄准
GAAs,我们采用了一种新的合成Notch“synNotch”受体系统,并开发了创新的T细胞。
在该系统中,仅在脑或GBM细胞上表达的第一抗原(例如EGFRvIII)引发
T细胞诱导识别IL-13 R α2和EphA 2的CAR的表达,从而根除GBM细胞
表达EphA 2或IL-13α2。我们的数据显示,EGFRvIII-synNotch引发的IL-13 R α2/EphA 2 CAR是
作为GBM特异性信号,EGFRvIII有效但限制性激活,导致完全根除
具有异质性EGFRvIII表达但不攻击IL-13 R α2/EphA 2-
CNS外的阳性细胞。此外,这些synNotch-CAR T细胞显著更有效,
比传统的组成型表达IL-13 R α2/EphA 2 CAR T细胞,
持久性(体内>100天)。总之,我们的数据表明,synNotch CAR T细胞可以彻底改变
通过克服肿瘤外毒性、抗原异质性和缺乏免疫原性,
坚持不懈我们的目标是建立良好生产规范的发展过程
EGFRvIII引发的IL-13 R α2/EphA 2 CAR T细胞的产物,以获得研究性新药(IND)
批准,并开发和进行I期临床试验的患者复发性GBM。在目标1中,我们
生产GMP级慢病毒载体,并建立GMP级慢病毒载体生产的标准程序。
EGFRvIII引发的IL-13 R α2/EphA 2 CAR T细胞。在目标2中,我们将完成体外和体内研究,
体外研究包括确认抗原特异性引发,特异性
细胞毒性和不存在可复制慢病毒。在体内,我们将确认临床前疗效,
毒理学、组织生物分布和植入以及synNotch CART细胞的持久性。在目标3中,
作为第一个人体1期临床试验,我们将确定synNotch CART细胞在
复发性EGFRvIII+ GBM患者。在随后的扩展队列中,在复发性EGFRvIII+的患者中,
GBM,我们将在手术前静脉内输注synNotch CART细胞,然后评估浸润,
和移植细胞在切除的GBM中的功能。这些研究将使我们能够确定最佳剂量
不仅基于耐受性,还基于药效学评估。
英文摘要
Development of safe and effective (CAR)-transduced T cell (CART) therapy for glioblastoma (GBM) needs to
overcome multiple challenges, including on-target off-tumor toxicity, heterogeneity of antigen expression, and
exhaustion of CART cells. There are no GBM-specific surface antigens that are uniformly present in tumor
tissue. Mutant epidermal growth factor receptor (EGFRvIII), for example, is GBM-specific but its expression is
heterogenous within the tumor. On the other hand, while non-mutant GBM-associated antigens (GAAs), such
as EphA2 and IL-13Rα2, are more uniformly expressed in GBM, their expression in other organs outside the
central nervous system (CNS) raises concern for off-tumor toxicity. As a way to safely and effectively target
GAAs, we have adopted a novel synthetic Notch “synNotch” receptor system and developed innovative T cells.
In this system, the first antigen, which is expressed exclusively on brain or GBM cells (e.g. EGFRvIII), primes
the T cells to induce expression of a CAR that recognizes IL-13Rα2 and EphA2, thereby eradicating GBM cells
expressing either EphA2 or IL-13α2. Our data show that EGFRvIII-synNotch primed IL-13Rα2/EphA2 CAR are
effectively but restrictedly activated by EGFRvIII as the GBM-specific signal, leading to complete eradication of
patient-derived xenografts with heterogeneous EGFRvIII expression but without attacking IL-13Rα2/EphA2-
positive cells outside of CNS. Furthermore, these synNotch-CAR T cells were significantly more efficacious
than conventional, constitutively expressed IL-13Rα2/EphA2 CAR T cells, and were associated with excellent
persistence (>100 days in vivo). Taken together, our data indicate that synNotch CAR T cells can revolutionize
the CAR T therapy for solid cancers by overcoming the off-tumor toxicity, antigen heterogeneity and lack of
persistence. Our goals are to establish the process for development of Good Manufacturing Practice
products of EGFRvIII-primed IL-13Rα2/EphA2 CAR T cells, to obtain an Investigational New Drug (IND)
approval, and to develop and conduct a phase I trial in patients with recurrent GBM. In Aim 1, we will
generate GMP-grade lentiviral vector and establish standard procedures for GMP-grade manufacturing of the
EGFRvIII-primed IL-13Rα2/ EphA2 CAR T cells. In Aim 2, we will complete both in vitro and in vivo studies that
are required for submission of an IND. In vitro studies include confirmation of antigen-specific priming, specific
cytotoxicity, and absence of replication competent lentivirus. In vivo, we will confirm preclinical efficacy,
toxicology, tissue biodistribution, and engraftment as well as persistence of synNotch CART cells. In Aim 3, in
a first-in-human phase 1 clinical trial, we will determine safety and toxicity of the synNotch CART cells in
patients with recurrent EGFRvIII+ GBM. In a subsequent expansion cohort, in patients with recurrent EGFRvIII+
GBM, we will infuse synNotch CART cells intravenously prior to surgery, and then evaluate infiltration, priming
and function of the infused cells in the resected GBM. These studies will allow us to determine optimal dosing
based not only on tolerability but also on pharmacodynamic assessments.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
-
批准号:10487528
-
项目类别:
-
资助金额:$25.37万
-
财政年份:2021
-
负责人:Hideho Okada
-
依托单位:
Development of novel synNotch CART cell therapy in adult patients with recurrent EGFRvIII+ glioblastoma
-
批准号:10689805
-
项目类别:
-
资助金额:$25.35万
-
财政年份:2021
-
负责人:Hideho Okada
-
依托单位:
Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression
-
批准号:10174862
-
项目类别:
-
资助金额:$36.94万
-
财政年份:2018
-
负责人:Hideho Okada
-
依托单位:
Glioma immunotherapy targeting IDH mutation-derived epitope and immunosuppression
-
批准号:10436184
-
项目类别:
-
资助金额:$36.2万
-
财政年份:2018
-
负责人:Hideho Okada
-
依托单位:
Preclinical development of breakthrough immunotherapy for brain tumors
-
批准号:10551829
-
项目类别:
-
资助金额:$72.53万
-
财政年份:2017
-
负责人:Hideho Okada
-
依托单位:
Preclinical development of breakthrough immunotherapy for brain tumors
-
批准号:10632441
-
项目类别:
-
资助金额:$14.54万
-
财政年份:2017
-
负责人:Hideho Okada
-
依托单位:
Preclinical development of breakthrough immunotherapy for brain tumors
-
批准号:10059272
-
项目类别:
-
资助金额:$72.53万
-
财政年份:2017
-
负责人:Hideho Okada
-
依托单位:
Preclinical development of breakthrough immunotherapy for brain tumors
-
批准号:10304142
-
项目类别:
-
资助金额:$72.53万
-
财政年份:2017
-
负责人:Hideho Okada
-
依托单位:
Phase I Vaccine Study using Brain Tumor Initiating Cells in WHO Grade II Gliomas
-
批准号:8754952
-
项目类别:
-
资助金额:$18.3万
-
财政年份:2014
-
负责人:Hideho Okada
-
依托单位:
Novel adoptive transfer therapy for glioma using CAR-transduced Type17 T-cells
-
批准号:8927697
-
项目类别:
-
资助金额:$39.63万
-
财政年份:2014
-
负责人:Hideho Okada
-
依托单位:
Phase I Vaccine Study using Brain Tumor Initiating Cells in WHO Grade II Gliomas
-
批准号:8934069
-
项目类别:
-
资助金额:$20.21万
-
财政年份:2014
-
负责人:Hideho Okada
-
依托单位:
Novel adoptive transfer therapy for glioma using CAR-transduced Type17 T-cells
-
批准号:8641010
-
项目类别:
-
资助金额:$39.52万
-
财政年份:2014
-
负责人:Hideho Okada
-
依托单位:
Type-1 Antigen Presenting Cells in CNS Tumors - Key to Efficient Anti-Tumor T-Cel
-
批准号:8518922
-
项目类别:
-
资助金额:$2.28万
-
财政年份:2012
-
负责人:Hideho Okada
-
依托单位:
Peptide-Based Vaccine Therapy for Childhood Malignant Gliomas
-
批准号:8020082
-
项目类别:
-
资助金额:$30.49万
-
财政年份:2010
-
负责人:Hideho Okada
-
依托单位:
Peptide-Based Vaccine Therapy for Childhood Malignant Gliomas
-
批准号:7887617
-
项目类别:
-
资助金额:$31.44万
-
财政年份:2010
-
负责人:Hideho Okada
-
依托单位:
A Bi-Institutional Pilot Study of Vaccinations for Patients with Low Grade Glioma
-
批准号:7730353
-
项目类别:
-
资助金额:$34.51万
-
财政年份:2009
-
负责人:Hideho Okada
-
依托单位:
A Bi-Institutional Pilot Study of Vaccinations for Patients with Low Grade Glioma
-
批准号:7879964
-
项目类别:
-
资助金额:$33.26万
-
财政年份:2009
-
负责人:Hideho Okada
-
依托单位:
Type-1 Antigen Presenting Cells in CNS Tumors - Key to Efficient Anti-Tumor T-Cel
-
批准号:7646821
-
项目类别:
-
资助金额:$23.34万
-
财政年份:2009
-
负责人:Hideho Okada
-
依托单位:
Giloma Vaccines in Combination with Poly-ICLC
-
批准号:7313416
-
项目类别:
-
资助金额:$32.48万
-
财政年份:2007
-
负责人:Hideho Okada
-
依托单位:
Novel Immunotherapy of Glioma using miR-17-92 Transfected T Cells
-
批准号:8956637
-
项目类别:
-
资助金额:$20.17万
-
财政年份:2007
-
负责人:Hideho Okada
-
依托单位:
海外基金