Tumor Immune Profiling to Optimize Clinical Trial Readiness in Basal Cell Nevus Syndrome
肿瘤免疫分析可优化基底细胞痣综合征的临床试验准备
基本信息
- 批准号:10046642
- 负责人:
- 金额:$ 20.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-21 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse eventAffectAllelesAnimal ModelAntibodiesAntitumor ResponseAreaBasal Cell Nevus SyndromeBasal cell carcinomaCD8-Positive T-LymphocytesCTLA4 geneCXCL10 geneCXCL9 geneCXCR3 geneCellsClinicalClinical ResearchClinical TrialsCytometryDataDendritic CellsDevelopmentDiseaseDisease remissionDouble-Blind MethodErinaceidaeFOXP3 geneFatal OutcomeFosteringFutureGenetic EngineeringGerm-Line MutationGrowthGrowth and Development functionHLA-DR AntigensHereditary DiseaseHumanImmuneImmune checkpoint inhibitorImmune responseImmunofluorescence ImmunologicImmunologic MonitoringImmunologicsImmunotherapeutic agentIndividualInfiltrationInflammatoryKnowledgeLaboratoriesLesionMHC Class I GenesMalignant NeoplasmsModelingMorbidity - disease rateMusMutationNeoplasm MetastasisNivolumabOperative Surgical ProceduresPTCH genePathogenesisPathologicPatientsPatternPeripheralPhenotypePlacebosPopulationPredispositionPropertyRandomizedReadinessRecurrenceRegulatory T-LymphocyteReportingResearchResistanceRhabdomyosarcomaRiskRoleSkinT-LymphocyteTestingThe SunTreatment EfficacyTreatment outcomeTumor BurdenTumor-infiltrating immune cellsWorkanti-PD-L1 therapyarmbasebench to bedsidechemokinechemokine receptorclinical developmentcostcytokineearly childhoodimmune checkpoint blockadeimmunogenicimmunoregulationimprovedinhibitor/antagonistmedulloblastomamouse modelneoplastic cellnovelnovel therapeuticsphase II trialpreclinical studypreventprogrammed cell death protein 1recruitresponseside effectskin disordersmoothened signaling pathwaytargeted agenttargeted treatmenttherapy outcometooltreatment strategytumortumor initiationtumor microenvironmenttumor progressiontumor-immune system interactionstumorigenic
项目摘要
SUMMARY
Germline mutations in PTCH underlie basal cell nevus syndrome (BCNS), a dominantly inherited disorder also
known as Gorlin-Goltz syndrome, in which affected individuals manifest accelerated Hh signaling, leading to
inordinate tumor burden that requires multiple, costly and often mutilating surgical procedures. Moreover, BCNS
patients develop multiple BCCs in sun-protected areas illustrating their unique tumor susceptibility. Except for
tumor-intrinsic Hh signaling, mechanisms underpinning the spontaneous growth and development of BCCs
remain unclear. Our group has fostered bench-to-bedside clinical trials with targeted agents in these patients,
ultimately leading to FDA approval of the SMO inhibitor (SMOi) vismodegib for treatment of advanced BCCs.
Despite substantial anti-tumor efficacy, a major challenge with SMOi has been the emergence of clinical
resistance and significant tumor recurrence, as well as intolerable side-effects causing half or more patients to
discontinue treatment. Additional preclinical and clinical studies from our group and others clearly indicate that
Hh signaling inhibition alone may be necessary but insufficient to permanently eradicate BCCs. This indicates a
need to develop novel treatment strategies to ameliorate the limitations of current SMOi’s to improve treatment
outcomes. Utilizing our genetically engineered Ptch1+/-/SKH-1 mouse model that faithfully recapitulates the
pathogenesis of human BCNS BCCs, we have demonstrated that (i) Hh signaling promotes accumulation of
FoxP3+ cells and increases pro-tumorigenic cytokines and chemokines in Ptch1-deficient skin; (ii) SMO inhibition
increases CD8+ cells and CXCL10/11, chemokines involved in T cell recruitment; and (iii) treatment of BCC-
bearing Ptch1+/-/SKH-1 with anti-PD-1 results in significant tumor regression. These data, together with recent
reports showing efficacy of immune checkpoint inhibitors (anti-CTLA4 or anti-PD-1) in human BCCs, strongly
support the role of immune mechanisms in BCC growth, and underscore the potential utility of combined SMO
and immune checkpoint blockade to reduce tumor burden. To facilitate a future multi-center, single-arm trial of
combined therapy of vismodegib and nivolumab (humanized monoclonal anti-PD-1 antibody) in BCNS patients,
this application aims to define tumor immune correlates relevant to BCNS microenvironments in Ptch1+/-/SKH-1
mice. In Aim 1, we will characterize immune cell populations and determine the immunologic mechanisms
relevant to Hh signaling, and in Aim 2, we will comprehensively define tumor immune profiles and elucidate
immunologic correlates predictive of anti-tumor responses to vismodegib and PD-1 blockade.
总结
项目成果
期刊论文数量(0)
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{{ truncateString('DAVID RINSEY BICKERS', 18)}}的其他基金
Molecular Mechanisms Underlying the Prevention of BCC Resistance
预防 BCC 耐药性的分子机制
- 批准号:
10552026 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Molecular Mechanisms Underlying the Prevention of BCC Resistance
预防 BCC 耐药性的分子机制
- 批准号:
10330598 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Molecular Mechanisms Underlying the Prevention of BCC Resistance
预防 BCC 耐药性的分子机制
- 批准号:
9974157 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Tumor Immune Profiling to Optimize Clinical Trial Readiness in Basal Cell Nevus Syndrome
肿瘤免疫分析可优化基底细胞痣综合征的临床试验准备
- 批准号:
10221074 - 财政年份:2020
- 资助金额:
$ 20.25万 - 项目类别:
Columbia University Skin Disease Resource-Based Center (epiCURE)
哥伦比亚大学皮肤病资源中心 (epiCURE)
- 批准号:
9087989 - 财政年份:2016
- 资助金额:
$ 20.25万 - 项目类别:
Columbia University Skin Disease Resource-Based Center (epiCURE)
哥伦比亚大学皮肤病资源中心 (epiCURE)
- 批准号:
9765045 - 财政年份:2016
- 资助金额:
$ 20.25万 - 项目类别:
Non-melanoma skin cancer: A model for impact of aging on an environmental disease
非黑色素瘤皮肤癌:衰老对环境疾病影响的模型
- 批准号:
9204120 - 财政年份:2016
- 资助金额:
$ 20.25万 - 项目类别:
Mechanism-based abrogation of BCC pathogenesis
基于机制的 BCC 发病机制的消除
- 批准号:
8460080 - 财政年份:2012
- 资助金额:
$ 20.25万 - 项目类别:
Mechanism-based abrogation of BCC pathogenesis
基于机制的 BCC 发病机制的消除
- 批准号:
8610310 - 财政年份:2012
- 资助金额:
$ 20.25万 - 项目类别:
Mechanism-based abrogation of BCC pathogenesis
基于机制的 BCC 发病机制的消除
- 批准号:
8296459 - 财政年份:2012
- 资助金额:
$ 20.25万 - 项目类别:
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