An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM
一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒,用于治疗 GBM
基本信息
- 批准号:10696185
- 负责人:
- 金额:$ 15.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-13 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAdult GlioblastomaAftercareAnimal ModelAnti-CD47Antibody TherapyAntibody titer measurementBindingBiological MarkersBiological ProductsBiopsyBloodBrainCD47 geneCD47-SIRPα blockadeCancer ControlCancer ModelCellsChemistryCirculationClinicalClinical TrialsCodeCollaborationsCorrelative StudyCytolysisDevelopmentDoseEatingEngineeringExtracellular FluidFDA approvedFc ReceptorFoundationsFutureG207GenesGlioblastomaGoalsGrowth FactorHalf-LifeHerpesviridaeHerpesvirus 1IgG1IgG4ImmuneImmune responseImmunocompetentImmunocompromised HostImmunologic Deficiency SyndromesImmunotherapyIn VitroInfusion proceduresInstitutionIntegral Membrane ProteinIntravenousInvestigational DrugsInvestigational New Drug ApplicationLengthLigandsMacrophageMalignant NeoplasmsMalignant neoplasm of brainMaximum Tolerated DoseMediatingMicrodialysisModelingMonitorMonoclonal AntibodiesMusNatural Killer CellsNeurologicOncolyticOncolytic virusesOrganOutcomePTPNS1 genePathologicPatientsPhagocytosisPhagocytosis InhibitionPhasePhase I Clinical TrialsProcessProtocols documentationRecommendationRecurrenceRoleSHPS-1 proteinSafetySignal PathwaySignal TransductionSimplexvirusSiteSystemTestingTherapeutic Monoclonal AntibodiesTissue HarvestingTissuesToxic effectTumor BurdenVirusVirus SheddingWorkanaloganti-tumor immune responseantibody immunotherapyantibody-dependent cell cytotoxicityantibody-dependent cellular phagocytosisbiomarker identificationcancer cellcancer typechemokinecohortcytokinedata sharingefficacy studygood laboratory practiceimprovedimproved outcomein vivoinnovationinsightintravenous administrationmanufacturemortalitymouse modelneoplastic cellnoveloncolysisoncolytic herpes simplex virusoncolytic virotherapyperipheral bloodphase 1 studypre-clinicalpreclinical safetypreclinical studyresponseresponse biomarkersafety outcomessafety studyscaffoldsmall molecule inhibitorsystemic toxicitytimelinetumortumor DNAtumor progression
项目摘要
PROJECT SUMMARY – PROJECT 1
The combination of oncolytic virotherapy (OV) and monoclonal antibody (mAb) immunotherapy has great
potential for the treatment of glioblastoma (GBM), the most common malignant brain tumor without a cure. An
OV carrying a mAb-coding gene can produce and release the mAb drug specifically at the tumor site as a safe,
effective, and innovative delivery system. Prior to our study, this approach has not been previously explored
using herpes simplex virus 1-based OV (oHSV). CD47 is a transmembrane protein widely expressed on cancer
cells including GBM. It acts as a “don’t eat me” signal by functioning as a ligand to signal regulatory protein-α
(SIRPα) expressed on macrophages, resulting in inhibition of phagocytosis. We have generated an oHSV that
expresses a full-length anti-CD47 mAb on an IgG1 scaffold (OV-αCD47-G1) that is capable of inducing antibody-
dependent cellular phagocytosis (ADCP) by macrophages and antibody-dependent cellular cytotoxicity (ADCC)
by natural killer cells to eradicate GBM cells in vitro and in vivo, in addition to blockade of the CD47-SIRPα “don’t
eat me” signaling pathway in macrophages. We have demonstrated that our novel OV-αCD47-G1 significantly
improves the survival of GBM-bearing mice in orthotopic, immunocompetent, and immunodeficient models. Our
central hypothesis is that OV-αCD47-G1 will be safe and effective at improving GBM treatment and its anti-
tumor activity in the brain will be reflected by markers in the peripheral blood. Importantly, we have optimized
and manufactured GMP-grade OV-αCD47-G1 to conduct the proposed studies and will initiate a phase I clinical
trial for adults with GBM. In this proposal, we will evaluate both the systemic and regional immune responses in
vivo following clinical-grade OV-αCD47-G1 administration and identify markers in the circulation that correlate
with anti-tumor activity in the brain in GBM animal models (Aim 1); we will perform Investigational New Drug
(IND)-enabling in vivo safety and efficacy studies using clinical-grade OV-αCD47-G1 (Aim 2); and we will
determine the safety of administering a single intracerebral infusion of OV-αCD47-G1 in adult patients with
recurrent GBM (Aim 3). To accomplish these objectives, we will utilize immunocompetent and
immunocompromised GBM mouse models for our correlative and preclinical studies evaluating OV-αCD47-G1
prior to the phase I clinical trial. Upon conclusion, we will understand how to optimize OV-αCD47-G1 therapy to
cure GBM. Further insight into this process, as will result from the implementation and completion of this
proposal, is impactful as it will ultimately lead to a reduction in mortality for adults suffering from GBM.
项目总结-项目1
项目成果
期刊论文数量(0)
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Jianhua Yu其他文献
Jianhua Yu的其他文献
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{{ truncateString('Jianhua Yu', 18)}}的其他基金
An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM
一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒,用于治疗 GBM
- 批准号:
10488216 - 财政年份:2021
- 资助金额:
$ 15.52万 - 项目类别:
An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM
一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒,用于治疗 GBM
- 批准号:
10306304 - 财政年份:2021
- 资助金额:
$ 15.52万 - 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
- 批准号:
10304873 - 财政年份:2019
- 资助金额:
$ 15.52万 - 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
- 批准号:
10063858 - 财政年份:2019
- 资助金额:
$ 15.52万 - 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
- 批准号:
9917605 - 财政年份:2019
- 资助金额:
$ 15.52万 - 项目类别:
scFvPD1-FLT3 CAR T Cells for the Treatment of Relapsed Acute Myeloid Leukemia
scFvPD1-FLT3 CAR T 细胞用于治疗复发性急性髓系白血病
- 批准号:
9765792 - 财政年份:2019
- 资助金额:
$ 15.52万 - 项目类别:
Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells
NK 细胞中新型 IL-15-AKT-XBP1s 通路的表征和靶向
- 批准号:
10520016 - 财政年份:2019
- 资助金额:
$ 15.52万 - 项目类别:
Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin
通过表达 E-钙粘蛋白的下一代 oHSV 克服病毒治疗的障碍
- 批准号:
9921509 - 财政年份:2018
- 资助金额:
$ 15.52万 - 项目类别:
Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin
通过表达 E-钙粘蛋白的下一代 oHSV 克服病毒治疗的障碍
- 批准号:
10544483 - 财政年份:2018
- 资助金额:
$ 15.52万 - 项目类别:
Elucidate and Modulate Cell Signaling in NK Cells for Glioma Treatment
阐明和调节 NK 细胞中的细胞信号传导用于神经胶质瘤治疗
- 批准号:
9240181 - 财政年份:2017
- 资助金额:
$ 15.52万 - 项目类别:
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