Modulating the PD-1/PD-L1 checkpoint to promote antitumor activity of HER2 CAR T cells in patients with sarcoma
调节PD-1/PD-L1检查点促进肉瘤患者HER2 CAR T细胞的抗肿瘤活性
基本信息
- 批准号:10562836
- 负责人:
- 金额:$ 66.78万
- 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:2023-03-07 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive TransferAdultAntigen TargetingAntigensAntitumor ResponseAutologousBiologyCAR T cell therapyCD19 geneCD8B1 geneCell LineCell SeparationCell TherapyCellsChemotherapy-Oncologic ProcedureChildClinicClinicalClinical ResearchClinical TrialsCombination immunotherapyCyclophosphamideDataDevelopmentDiseaseDoseDown-RegulationERBB2 geneEngineeringEventFunctional disorderFutureGoalsHematologic NeoplasmsImmuneImmune checkpoint inhibitorImmune signalingImmunologic MarkersImmunotherapyIn complete remissionInfusion proceduresInterventionInvestigational DrugsInvestigational New Drug ApplicationKineticsKnowledgeLiteratureMalignant NeoplasmsObservational StudyOutcomePD-1 blockadePD-1/PD-L1Patient SelectionPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsPredispositionPropertyPublic HealthROR1 geneRecurrenceRecurrent diseaseRefractoryRelapseReportingResearchResearch PersonnelRhabdomyosarcomaSafetySerumSignal TransductionSolid NeoplasmT cell responseT-Cell ReceptorT-LymphocyteTestingTherapeuticToxic effectTransgenesTreatment outcomeTumor AntigensTumor EscapeTumor PromotionTumor TissueUp-Regulationanti-PD1 antibodiesantitumor effectbiomarker identificationcell mediated immune responsecheckpoint inhibitionchemotherapychildhood sarcomachimeric antigen receptor T cellsclinical efficacyclinical predictorscohortdesignfludarabineimmune cell infiltrateimmune checkpointimmune checkpoint blockadeimprovedinnovationnovel strategiesperipheral bloodphase 1 studyphase I trialpreclinical studypredictive markerprogrammed cell death ligand 1programmed cell death protein 1prospectiverational designreceptorresearch clinical testingresponsesarcomasuccesstreatment responsetumortumor microenvironmentyears of life lostyoung adult
项目摘要
PROJECT SUMMARY/ABSTRACT
Immunotherapy has shown limited efficacy against pediatric sarcoma. In our recently completed phase I study,
infusion of HER2-targeted chimeric antigen receptor T cells (CAR-T) was safe and showed encouraging
indicators of antitumor activity, including three durable complete responses. The key observations from this study
are: (1) lymphodepletion promotes CAR-T expansion but only marginally improves persistence, (2) adoptively
transferred CAR-T are susceptible to immune inhibition, and (3) antigen downregulation/loss is associated with
disease relapse. While the literature is lacking on immune inhibitory mechanisms and tumor adaptations in
sarcoma, our findings are in line with observations made by others in early clinical and pre-clinical studies of
cellular therapy for solid tumors. Our long-term goal is to develop new approaches that capitalize on expected
tumor defenses which may be key to unleashing the potential of CAR-T against sarcomas and other solid tumors.
Therapeutic approaches that integrate strategies to address these compensatory mechanisms up front may
mitigate downstream tumor escape and relapse. The objective of this project is to conduct prospective clinical
testing of HER2 CAR-T in combination with PD-1/PD-L1 checkpoint disruption strategies in a disease-specific
cohort. The central hypothesis is that the combination immunotherapy will promote immune infiltration, remodel
the tumor microenvironment, alleviate CAR-T dysfunction, and thereby improve antitumor responses. Our
specific aims will test the following hypotheses: (Aim 1) The combination of anti-PD-1 antibody and HER2 CAR-
T administered after lymphodepletion is safe in patients with sarcoma, will improve CAR-T kinetics, and will elicit
antitumor responses; (Aim 2) Cellular and serum-based studies in treated patients will help identify biomarkers
of toxicity and response; and (Aim 3) Engineering CAR-T to positively transform the PD-1/PD-L1 interaction in
the tumor microenvironment will potentiate antitumor effects of the cellular product while incorporating design
attributes to enhance its safety . We will evaluate Aims 1 and 2 through implementation of a phase I study of
autologous HER2 CAR-T and anti-PD-1 antibody after cyclophosphamide and fludarabine lymphodepletion in
patients with sarcoma (HEROS 3.0 clinical trial). In Aim 3, we will develop an investigational new drug (IND) for
HER2 CAR-T co-expressing a PD-1 checkpoint reversal receptor (CPR). At the conclusion of the project, we will
understand if CAR-T can be safely administered with immune checkpoint inhibition to improve treatment
outcomes for children and young adults with sarcoma. The significance of these contributions are: (1)
establishing the clinical utility of combination immunotherapy for sarcoma, (2) potentially identifying “modifiable”
patient- and treatment-related factors to guide future improvements to CAR-T therapy, and (3) enabling clinical
testing of an innovative CAR-T platform. This knowledge is critical to advancing the field, as recurrent or
refractory sarcomas remain largely incurable.
项目总结/文摘
项目成果
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