肾细胞癌细胞疗法的新靶点.pdf

1、Novel Targets for CellularTherapies in RCCRosa Nadal Rios.MD.PhD.Associate ProfessorUniversity of Washington School of MedicineFred Hutch Cancer CenterDifferent Tumor Antigen TypesTumor AntigensTumor AntigensExpression in Expression in normal tissuesnormal tissuesSimilarities Similarities to normal

2、proteinsto normal proteinsShared Shared among among patients?patients?Clinical experienceClinical experienceTAAsTAAsCGAslimitedlimitedhighhighyesyes:NY-ESO-1HERVvariablevariablelowlowyeslimited:HERVHERV-E ETDAsyesyeshighhighyesyes:MART-1Overexpressed Agyesyeshighhighyesyes:CAIX,CD70.CD70.TSAs TSAs m

3、SNVsnomoderaterarelyyes:KRASG12DINDELSnolowlowrarelylimitedGene fusionsnolowlowrarelylimited:SYT-SSXViral oncoproteinsnolowlowyesyesUCAsSplice variants,alternative ORFs,post-translational modificationsunexplored,some expressed in normal cellsvariableunexplorednoTAAs:tumor-associated antigens.TSAs:tu

4、mor-specific antigens.CGAs:cancer germline antigens.TDAs:tissue differentiation antigens.Ag:antigen.mSNVs:missense single-nucleotide variants.UCAs:Unconventional antigens Antigenic Landscape Tumor mutational burden lowIndels(12%)Transcriptional activation of HIFCAIXVEGFRCD70HERV-E=ERV-4AXLROR2MUC1Lo

5、ss of epigenetic tumor suppressorsCGA?HERV?HERV:human endogenous retroviruses,CGA:cancer germline antigensChromothripsis Shapiro,D.D.Cancers.2023.Turajlic,S.Cell.2018.Cubas,AA.Nat RevUrol.2018.Ricketts,C.J.Cell.2018.Braun,D.A.Nat Rev Clin Oncol.2021Target Target AntigenAntigenCARCAR-T vs T vs TCRTCR

6、Cell SourceCell SourceGene TransferGene TransferPhasePhasen nDataDataStatusStatusNCT&RefNCT&RefCAIXCAR-TAutologousRVI/II12LFT abnormalitiesNo ResponsesTerminatedLammers,CH et al.Mol Ther.2013CAIXCAR-T+G250Autologous-INANAEnrollingNCT04969354VEGFR-II CAR-TAutologousRVI/II23RCCMelPR:1,SD:1,PD:21Termin