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Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer

Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer
IFNAR1 信号传导对癌症 CAR T 细胞治疗的预后和治疗意义
批准号:
10215845
负责人:
Matthew John Atherton
金额:
$15.37万
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
项目状态:
未结题
起止时间:
2021-07-01 至 2026-06-30
关键词:
Adoptive Cell TransfersAntigensAutologousAwardB lymphoid malignancyB-Cell LymphomasB-Cell NeoplasmB-LymphocytesBiologicalBlood Component RemovalCD19 geneCancer PatientCanis familiarisCell CountCell TherapyCell surfaceCellsCessation of lifeChronic Lymphocytic LeukemiaClassificationClinicalClinical TrialsDataDevelopmentDevelopment PlansDown-RegulationEnrollmentExposure toFc ReceptorFeverFoundationsFutureGenerationsGeneticHumanIFNAR1 geneImmune responseImmunologicsImmunologyImmunotherapeutic agentIn VitroIn complete remissionInfusion proceduresInterferon ReceptorInterferon Type IInterferonsKnowledgeMalignant NeoplasmsMalignant lymphoid neoplasmMeasurableMediatingMemoryModelingMusNeoplasmsOncologistOutcomePatient-Focused OutcomesPatientsPennsylvaniaPharmacologyPhenotypePilot ProjectsPlayPre-Clinical ModelPrimary NeoplasmPrognostic MarkerPublishingRefractoryResearchRodentSafetyScientistSecureSignal TransductionSolidSurfaceT cell therapyT memory cellT-Cell ActivationT-Cell DevelopmentT-Cell ProliferationT-Cell ReceptorT-LymphocyteTechniquesTestingTherapeuticTimeTractionTrainingTreatment EfficacyTumor-Infiltrating LymphocytesUbiquitinationUniversitiesanti-tumor immune responseblood productcancer therapycareer developmentchimeric antibodyclinical predictorscytokine release syndromeefficacy evaluationgenetic signatureimprovedimproved outcomein vivoinhibitor/antagonistinnovationinsightlarge cell Diffuse non-Hodgkin&aposs lymphomamouse modelmutantp38 Mitogen Activated Protein Kinasepilot trialpre-clinicalpre-clinical assessmentpreclinical efficacyprognosticprognostic significanceresponsesuccesstraittrial designtumortumor progressiontype I interferon receptor

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中文摘要
翻译
过继细胞疗法(ACT)已经彻底改变了某些恶性肿瘤的治疗和反应
英文摘要
Adoptive cellular therapy (ACT) has revolutionized the treatment of certain malignancies and responses in refractory B cell tumors treated with chimeric antibody receptor (CAR)-expressing T cells have been remarkable. However, ACT is not consistently curative even in these particularly responsive cancers, highlighting the critical need for innovative approaches to improve this powerful therapeutic approach. Type I interferon (IFN) signaling through the type I interferon receptor (IFNAR) plays a key role in the activation, differentiation and function of T cells. Importantly, degradation of the type I interferon receptor chain subunit 1 (IFNAR1) in anti-tumor T cells favors tumor progression whereas its genetic or pharmacologic (by p38 inhibition) stabilization improves anti-tumor T cell activity in mouse models. While rodent studies have yielded much preclinical insight into CAR T cells, they fail to accurately predict clinical safety and efficacy. However, genetically outbred and immunologically intact canine cancer patients that develop tumors spontaneously are rapidly gaining traction as an invaluable preclinical model. In exciting new preliminary data, we infused CAR T cells treated with the IFNAR1 stabilizing p38 inhibitor ralimetinib into a canine B cell lymphoma patient. Following treatment, we observed signs associated with CAR T cell mediated anti-tumor activity that have not been previously observed in canine patients treated with CAR T cells. Furthermore, in human chronic lymphocytic leukemia patients, an active type I IFN gene signature was associated with improved outcomes following CAR T cell therapy. Together, these data support the hypothesis that stabilization of IFNAR1 on the surface of CAR T cells will improve their therapeutic efficacy for the treatment of B cell malignancies. We will perform the following studies to test this: 1. Canine cancer patients with spontaneous diffuse large B cell lymphoma currently being enrolled in a pilot trial will be used to determine the safety and efficacy of IFNAR1-stabilized CART cells. 2. CART cells derived from multiple species will be evaluated in vitro and in vivo to ascertain the mechanism by which genetic and pharmacologic IFNAR1 stabilization enhances the anti-tumor activity of CART cells. 3. The prognostic significance of IFNAR1 and downstream signaling in T cell apheresis products used to manufacture CAR T cells and CAR T cells themselves will be evaluated in patients with B cell malignancies. We anticipate that IFNAR1 stabilization will safely enhance the activity of CAR T cells. As a veterinary oncologist with doctoral training in immunology I have a solid foundation of the knowledge and skillsets required to undertake these studies. The proposed research on the application of CART cell therapy for the treatment of B cell neoplasia will be performed under the expert guidance of Ors. Fuchs and Mason and represents a field for which the University of Pennsylvania is globally renowned.
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Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer
  • 批准号:
    10657328
  • 项目类别:
  • 资助金额:
    $15.37万
  • 财政年份:
    2021
  • 负责人:
    Matthew John Atherton
  • 依托单位:
Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer
  • 批准号:
    10370427
  • 项目类别:
  • 资助金额:
    $15.37万
  • 财政年份:
    2021
  • 负责人:
    Matthew John Atherton
  • 依托单位:
国内基金
海外基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2022
  • 负责人:
    王亚伟
  • 依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究