Flt3l gene-modified cDC1 in situ vaccination in NSCLC: mechanisms and therapeutic application
Flt3l 基因修饰的 cDC1 原位疫苗接种在 NSCLC 中的作用:机制和治疗应用
基本信息
- 批准号:10585591
- 负责人:
- 金额:--
- 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:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdverse eventAffectAgeAntibodiesAntigen PresentationAntigensApoptoticAuthorization documentationAutologousAutomobile DrivingBioinformaticsCCL21 geneCD8-Positive T-LymphocytesCXCR6 geneCancer EtiologyCancer ModelCell SurvivalCell secretionCellsCellular immunotherapyCessation of lifeClinicalClinical SciencesClinical TrialsCombined Modality TherapyCross PresentationCytokine GeneDataData ScientistDendritic Cell VaccineDendritic CellsDependenceDevelopmentDiseaseDoctor of PhilosophyEngineeringEthicsEvaluationEvolutionFLT3 geneFLT3 ligandFlow CytometryFundingGene Expression ProfilingGene ModifiedGoalsGrantHealth systemHealthcare SystemsImmuneImmune checkpoint inhibitorImmune responseImmunobiologyImmunofluorescence ImmunologicImmunologic MemoryImmunologic SensitizationImmunologyImmunophenotypingImmunosuppressionImmunotherapyIn VitroIn complete remissionIncidenceInjectionsInstitutionInternationalK-Series Research Career ProgramsLigandsLos AngelesMalignant neoplasm of lungManuscriptsMediatingMediatorMentorsMolecularMusMutationNatural Killer CellsNatureNon-Small-Cell Lung CarcinomaPTPRC genePathway interactionsPatientsPhenotypePhysiciansPopulationPreparationProteinsRefractoryResearchRoleSTK11 geneScientistSpleenStable DiseaseSurvival RateT cell clonalityT cell responseT-Cell ActivationT-LymphocyteT-cell receptor repertoireTherapeuticTrainingTranslational ResearchTumor AntigensTumor ImmunityTumor PromotionTumor-Infiltrating LymphocytesVaccine TherapyVaccinesVeteransWritinganti-PD-1antigen-specific T cellsauthoritybeta Chain Antigen T Cell Receptorcancer immunotherapycancer infiltrating T cellscareer developmentcheckpoint inhibitionchemokineclinical translationclinically relevantcongeniccytokinedraining lymph nodeexome sequencingexperienceimmune resistanceimprovedin situ vaccinationin vivoinnovationinterestmilitary veteranmouse modelneoantigensnovelnovel strategiesnovel vaccinespartial responsepatient subsetspembrolizumabphase I trialpreclinical studyprogrammed cell death ligand 1rational designresistance mechanismresponserestorationsingle-cell RNA sequencingstemsynergismtertiary lymphoid organtraffickingtranscriptome sequencingtranslational research programtumortumor immunologytumor microenvironmentvaccine evaluation
项目摘要
PROJECT SUMMARY/ABSTRACT
Dr. Salehi-Rad is a Staff Pulmonologist at the VA Greater Los Angeles Healthcare System (VA GLAHS)
with a clinical and research interest in lung cancer, the leading cause of cancer death among U.S. Veterans. In
applying for the VA Career Development Award (CDA-2), Dr. Salehi-Rad’s goal is to establish an independent
translational research program at the VA GLAHS, focused on improving our understanding of the
immunopathogenesis of lung cancer for the development of novel approaches for cancer immunotherapy. He is
supported by Steven Dubinett, MD (Primary-Mentor), a renowned VA Merit-funded physician-scientist and a
leading expert in lung cancer, Antoni Ribas, MD, PhD (Co-Mentor), an internationally recognized authority in
cancer immunology, and Paul Boutros, PhD (Co-mentor), a distinguished data scientist. Mentors were identified
based on their complementary scientific expertise for the proposed research and their extensive experience in
mentoring academic physician-scientists. Through UCLA Clinical and Translational Science Institute (CTSI), Dr.
Salehi-Rad will have access to numerous career development seminars that address such topics as grant
writing, manuscript preparation, and ethical research. He will also take graduate courses to obtain further training
in immunology and bioinformatics. Dr. Salehi-Rad will have the full institutional support of both the VA and UCLA
Health Systems to carry out his research.
Dr. Salehi-Rad has established clinically relevant murine models of NSCLC with increased mutational
burden and identified a novel targetable mechanism of resistance to immunotherapy in LKB1-deficient NSCLC.
Utilizing these murine models, Dr. Salehi-Rad has shown that in situ vaccination (ISV) with elite antigen cross-
presenting conventional type 1 DCs that are gene-modified to secrete FMS-like tyrosine kinase 3 ligand (FLT3L-
cDC1), a cytokine that promotes DC viability and expansion, sensitize immune refractory NSCLC to immune
checkpoint inhibition (ICI). In this proposal, Dr. Salehi-Rad aims to study the immune mechanisms of DC ISV.
Aim 1.1 builds on preliminary in vitro data indicating enhanced viability of FLT3L-cDC1 compared to cDC1 and
seeks to determine the molecular mechanisms that result in increased survival of FTL3L-cDC1. Aim 1.2 & 1.3
utilize various murine models to determine the vaccine and endogenous DC viability, antigen trafficking and
antigen-specific T cell priming following DC ISV. Aim 2 of the proposal focuses on elucidating the immune
determinants of response to DC ISV as monotherapy or as a combination therapy with ICI. Aim 2.1 & 2.2
combine single cell immunophenotyping by flow cytometry and single cell RNA-sequencing (scRNA-seq) with
spatial analysis by multiplex immunofluorescence (MIF) to develop a comprehensive understanding of the local
and systemic immune responses induced by DC ISV. Aim 2.3 utilizes antibody depletion studies to evaluate the
dependency of DC ISV on T cells and natural killer cells. Aim 3 will determine the evolution of T cell repertoires
by TCR-β CDR3 sequencing and tumor-neoantigen profiles by whole-exome sequencing (WES) to assess
whether DC ISV induces the expansion of the TCR repertoire and promotes tumor immunoediting. Improved
understanding of the nature of immunosuppression in NSCLC and the immunostimulatory mechanisms of DC
ISV will represent a significant contribution to the field of lung cancer immunology and could facilitate the clinical
translation of FLT3L-cDC1 ISV as an innovative therapeutic strategy for this devastating disease that affects
many of our Veterans.
项目总结/文摘
项目成果
期刊论文数量(0)
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