A Phase II Clinical Trial in Newly Diagnosed Glioblastoma Patients Treated with WP1066 and Radiation
新诊断的胶质母细胞瘤患者接受 WP1066 和放射治疗的 II 期临床试验
基本信息
- 批准号:10658700
- 负责人:
- 金额:$ 60.18万
- 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:2023-05-05 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelAnimalsAntigen PresentationAntigen-Presenting CellsAntitumor ResponseBlood - brain barrier anatomyBrainBrain NeoplasmsBrain Stem GliomaCD11c AntigensCD3 AntigensCell physiologyCellsCellular immunotherapyChildhoodClinicalClinical TrialsCombined Modality TherapyDendritic CellsDendritic cell activationDependenceDoseDrug KineticsEducationEffectivenessExcisionFlow CytometryGlioblastomaGliomagenesisGoalsHeterogeneityHigh Pressure Liquid ChromatographyHumanImmuneImmune responseImmune systemImmunocompromised HostImmunohistochemistryImmunologicsImmunosuppressionImmunotherapyInfiltrationInflammatory ResponseLesionMGMT geneMagnetic Resonance ImagingMalignant NeoplasmsMapsMemoryMetastatic malignant neoplasm to brainMicrogliaModelingMusMyeloid CellsNatural ImmunityNewly DiagnosedOperative Surgical ProceduresOutcomePathway interactionsPatientsPharmaceutical PreparationsPhase I Clinical TrialsPhase II Clinical TrialsPhenotypePopulationProgression-Free SurvivalsRadiationRadiation therapyRecurrenceResearchSignal InductionStat3 proteinT cell infiltrationT-Cell ActivationT-LymphocyteTestingTextureTissuesUniversitiesValidationadaptive immunitycancer cellcohortfirst-in-humanimmune activationimmune clearanceimmunogenicityimprovednano-stringneuro-oncologypharmacodynamic biomarkerpharmacologicphase 3 studyphase I trialphase II trialpre-clinicalpreclinical studyradiological imagingresponsesmall molecule inhibitorstandard of caretumortumor microenvironmenttumor-immune system interactions
项目摘要
SUMMARY
The brain tumor microenvironment (TME) is dominated by myeloid cell infiltrates which are mostly brain resident
microglia and infiltrating glioblastoma-associated myeloid cells (GAMs). Despite this fact, most clinical trials for
glioblastoma have been directed to T cell-based immunotherapies, which have failed to impact outcome for most
patients. Targeting glioblastoma based on re-education of GAMS to enable immunological clearance is the goal
of this clinical trial. The signal transducer and activator of transcription 3 (STAT3) is a negative regulator of both
innate and adaptive immunity and this pathway is markedly up regulated in the TME. We have previously
developed and tested, in the context of Phase I clinical trials, a first-in-man blood-brain-barrier penetrant small
molecule inhibitor of STAT3, designated WP1066. The Phase I trial results have shown that WP1066 is well
tolerated and is inhibiting the STAT3 target in immune cells. As a monotherapy, WP1066 treatment has
demonstrated the ability to stimulate robust anti-tumor response in multiple preclinical studies that is further
enhanced with radiation therapy, which is standard of care for newly diagnosed glioblastoma and is known to
increase tumor immunogenicity. Unbiased nanostring analysis of treated tumors revealed that activation of
antigen presentation in the TME with the combination treatment. For the research proposed here we want to
extend our preclinical findings to newly diagnosed glioblastoma patients. In this clinical trial, we will test the
hypothesis that the administration of WP1066 with radiation will induce T cell-dendritic cell cluster interactions in
the glioblastoma microenvironment, and this induction, in turn, will increase progression free survival (PFS) for
glioblastoma patients. In specific Aim 1, we conduct a Phase II trial with an expansion cohort for the combination
of WP1066 and radiation in newly diagnosed MGMT unmethylated glioblastoma patients. In cohort 1, newly
diagnosed MGMT unmethylated, IDH1 wild-type glioblastoma patients will be treated with 8 mg/kg of WP1066
while undergoing standard-of-care radiation therapy at a daily dose of 2 Gy. PFS will be used to ascertain if there
is indication of treatment benefit. In cohort 2, patients for whom gross total resection was not achieved will be
treated with the combination of radiation and WP1066 with the intent of obtaining treated tumor, if a surgically
amenable lesion is present. Such tissue would allow for analysis of TME immune activation and cluster
interactions, drug concentrations and target engagement in Aim 2. Aim 2 will also use longitudinal textural MRI
analysis to correlate inflammatory responses in the TME by using our STAT3-specific multiplex immune
fluorescent panel and complementary ex vivo flow cytometry and nanostring profiling. STAT3 target inhibition,
including within specific immune cell populations, will be ascertained through use of the multiplex panel, which
will also inform regarding the induction of cluster interactions in the tumor. HPLC quantification of WP1066
concentrations in both enhancing and non-enhancing tumor will be used to determine drug pharmacokinetics. In
Aim 3, we will clarify which human GAMs in the TME trigger T cell activation, and if such activation is altered by
STAT3 inhibition.
总结
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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Amy Beth Heimberger其他文献
Amy Beth Heimberger的其他文献
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{{ truncateString('Amy Beth Heimberger', 18)}}的其他基金
Fgl2 neutralizing therapy for inducing tumor specific brain resident immune memory against CNS tumor relapse
Fgl2中和疗法诱导肿瘤特异性脑常驻免疫记忆对抗中枢神经系统肿瘤复发
- 批准号:
10655501 - 财政年份:2021
- 资助金额:
$ 60.18万 - 项目类别:
Fgl2 neutralizing therapy for inducing tumor specific brain resident immune memory against CNS tumor relapse
Fgl2中和疗法诱导肿瘤特异性脑常驻免疫记忆对抗中枢神经系统肿瘤复发
- 批准号:
10275974 - 财政年份:2021
- 资助金额:
$ 60.18万 - 项目类别:
Fgl2 neutralizing therapy for inducing tumor specific brain resident immune memory against CNS tumor relapse
Fgl2中和疗法诱导肿瘤特异性脑常驻免疫记忆对抗中枢神经系统肿瘤复发
- 批准号:
10454240 - 财政年份:2021
- 资助金额:
$ 60.18万 - 项目类别:
STINGing GBM: A First-in- Man Clinical Trial in Surgical Resectable Recurrent GBM
刺痛 GBM:可手术切除复发性 GBM 的首次人体临床试验
- 批准号:
10626394 - 财政年份:2018
- 资助金额:
$ 60.18万 - 项目类别:
Fgl-2 targeted therapy for reversing multi-modality immune suppression
Fgl-2靶向治疗逆转多模式免疫抑制
- 批准号:
9152967 - 财政年份:2016
- 资助金额:
$ 60.18万 - 项目类别:
Targeting Malignant Gliomas with a Novel Inhibitor of the STAT3 Pathway
用 STAT3 通路的新型抑制剂靶向恶性胶质瘤
- 批准号:
8588570 - 财政年份:2008
- 资助金额:
$ 60.18万 - 项目类别:
Targeting Malignant Gliomas with a Novel Inhibitor of the STAT3 Pathway
用 STAT3 通路的新型抑制剂靶向恶性胶质瘤
- 批准号:
8753979 - 财政年份:2008
- 资助金额:
$ 60.18万 - 项目类别:
Targeting Malignant Gliomas with a Novel Inhibitor of the STAT3 Pathway
用 STAT3 通路的新型抑制剂靶向恶性胶质瘤
- 批准号:
9339983 - 财政年份:2008
- 资助金额:
$ 60.18万 - 项目类别:
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