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Saturday,May 4,20241MolecularImagingofTherapeuticCells:Pre-ClinicalandClinicalStudiesShahriarYaghoubi,Ph.D.ChiefScientificOfficerCellSightTechnologies,Inc.OutlineBackgroundNon-invasiveCellImagingTechniquesCellTransplantationImagingCellTraffickingImagingClinicalReporterGeneImagingofAdoptivelyTransferredTherapeuticCells Repeatedlyimagethelocation(s)ofoneormorespecificpopulationofcellsofinterestanddeterminecellquantityatalllocationsinlivingsubjectsRepeatedlyimagethe“status”ofpopulationsofcells inlivingsubjectsincludingpotentialinteractionswithothercellsDonotsignificantlyperturbthecellswhilerepeatedly imagingthemAllowsmoothtransitionfrompre-clinicaltoclinicalmodelsCellular Imaging Wish ListMethods for Imaging Therapeutic Cells in Living SubjectsDirectLabelingwithanImagingProbe:111In-Oxine,64Cu-PTSM,Ferridex,NanoparticlesIncorporationofaConstitutivelyExpressedImagingReporterGeneThroughTransduction,Transfection,Electroporation,etc,thenImagingatMultipleTimePointswithaReporterProbeUsingaHighlySpecificProbetoImageProductsofaGeneSolelyExpressedbytheTargetCells:mRNA,Protein(Enzyme,SurfaceReceptor)Direct Labeling Strategies111In CIK SPECT 24 hours42 hoursPre-CIK 18F FDG PETImaging Trafficking of Cytokine Induced Killer Cells with 111In-OxineSpleenLiverReporter Gene Based Therapeutic Cell ImagingReporter Gene StrategiesGreenFluorescentProtein(Fluorescence)RedFluorescentProtein(Fluorescence)FireflyLuciferase(Bioluminescence)RenillaLuciferase(Bioluminescence)GaussiaLuciferase(Bioluminescence)HerpesSimplexVirusType1ThymidineKinase(PET/SPECT)DopamineType2Receptor(PET)Sodium-IodideSymporter(PET/SPECT)Somatostatintype2Receptor(PET/SPECT)TransferrinReceptor(MRI)Reporter Gene Imaging with BioluminescenceOptical ImagingPositron Emission Tomography511keVnucleuspositronscattersintissuelosingenergye+511keVannihilatione+e+e+e+ecoincidence?yesEnzyme Based PET Reporter Gene ImagingAd-CMV-HSV1-sr39tk18F-FHBGReporter Gene Imaging with microPET GambhirS.S.et.al.,JNM2019,PNAS2000,2019fl/hrlegfp/rfp/mrfp1 ttk/wttkLENSHASAGYQASTTAGPGSATCMVReporterGenes:Bioluminescence:vFireflyluciferase(fl)vSyntheticrenillaluciferase(hrl)Fluorescence:vEnhancedGreenFluorescenceprotein(egfp)vRedFluorescenceProtein(rfp)vMonomericRedFluorescenceProtein(mrfp1)PET:vDeletionmutantofHSV1-sr39tk(ttk)vDeletionmutantofWildtypeHSV1-tk(wttk)Ray et.al.,Cancer Research(March 2019)Tri-fusionMultimodalityReportersTri-fusionMultimodalityReportersFluorescencemicroPETRay et.al.,Cancer Research(March 2019)CellBioluminescenceClinicalPETTrafficking of Imaging Trafficking of T Cell Hybridomas Stably Expressing a Triple Fusion Reporter Gene inCollagen Induced Arthritic MiceYaghoubietal.JBiomedOptics12(6):064025-1(2019)Cell Transplantation ImagingCell TransplantationMicroPET ImagingHistologyAutoradiographyWuet.al.,Circulation,Sept.2019Day50%ID/g1%ID/g10864201030%ID/g0.5%ID/g1086420105108642010510864201061086420106ControlDay10Day15Day20P/s/cm2/srP/s/cm2/srP/s/cm2/srP/s/cm2/srP/s/cm2/srAImaging ES Cell Survival&ProliferationCao F,et al.Circulation 2019;113:1005-1014Ablation of Cellular“Misbehavior”withTK Suicide Gene TherapyThymidinekinaseservesasaPETreportergenewhen18F-FHBGPETreporterprobeisusedinpico-nanomolarconcentration.Thymidinekinaseservesassuicidegenewhenganciclovirisadministeredinmilligramdosages.CaoF,etal.Circulation2019;113:1005-1014CellTraffickingImagingU251T-rLuc+GBMINTRACRANIALXENOGRAFTHUMANT-CELLSAdministeredI.V.TUMORSIGNALSYSTEMICALLYADMINISTEREDT-CELLSHOMETOINTRACRANIALGLIOMAT-CELLSIMAGEDSERIALLY48hrs 72hrs 96hrs T-CELLSIGNALM.Jensen(CityofHope)TowardsClinicalImagingofCellTransferPRG/PRPSystem(EnzymeBased)18FFHBGHSV1-sr39TK18FFHBG9-4-18FFluoro-3-(hydroxymethyl)butylguanineImaging hMSC Transduced with Adenoviral Vectors Carrying HSV1-sr39tkLRL18F-FDG18F-FHBG18F-FHBGPET/CTYaghoubietal.NatureClinicalPracticeOncology6(1):53-58(2009)Penuelas.et.al.Gastroenterology128:1787-95(2019)HumanHSV1-tkReporterGeneImagingImaging Cytolytic T Cells in Glioma PatientsLeukapheresisSeparationofMononuclearCellsActivationofAutologousTCellsExpandwithIL-2hCMVHyTKhEF1 IL-13 ElectroporationSelectionOfClonesWithHygromycinIL-13+,CD8+,TCR/+,SinglecopyofplasmidDNA,IL-2dependent,SusceptibletoGCVinducedcelldeathExVivoExpansionwithIL-2Infusions12sessions107108cellsReporterGeneBasedImagingofTherapeuticCells(FirstClinicalDemonstration)Yaghoubi et al.Nature Clinical Practice Oncology 6(1):53-58(2009)18FFHBGActivityatCTLInfusionSite,BeforeandAfterInfusionsintheSamePatientPost-CellPre-Cell18FFHBGBrainPETSuperimposedOverBrainMRIStandardUptakeValues(SUV)MaxIntensityinRegionsofInterest(ROI)Max SUV Tumor to Background RatiosPercentChangein18FFHBGAccumulationandTumor/BKGD18FFHBGPostCTLInfusion MultimodalityImagingApproachesShouldHelpTransitionfromPre-ClinicaltoClinicalNon-invasiveCellImagingStudiesDirectLabelingandReporterGeneBasedImagingStrategiesareAvailableforMonitoringTherapeuticCellBiodistributioninPatientsReporterGeneBasedTechniquesAllowImagingBiodistributionasWellasSurvivalandStatusIncorporatingNon-InvasiveImagingIntoCellTherapyTrialsShouldHelpOptimizeProtocolsandPredictEfficacyorPotentialAdverseEffectsSummary&Future DirectionsAcknowledgementsStanfordUniversitySanjivGambhirMultimodalityImagingGroupNuclearMedicineClinicCyclotronCityofHopeNationalMedicalCenterMichaelJensenGroupUCLAMedicalCenterDeptofMolMedPharmacologyNuclearMedicineClinicCyclotronFundingNationalCancerInstituteICMICp50R01PatientVolunteers5/4/202435谢谢你的阅读v知识就是财富v丰富你的人生xiexie!xiexie!谢谢！谢谢！
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