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1、2023胰腺导管腺癌靶向及免疫治疗进展（全文）摘要胰腺导管腺癌（PDAC）是一种侵袭性癌症，诊断时多为晚期，治疗手段有限，全身化疗只能带来局限的治疗效果。本文研究者系统回顾了针对不同PDAC分子亚型的靶向治疗和免疫治疗进展。聚焦当前支持这些治疗方法的临床前和临床证据，以及组合疗法改善PDAc患者生活质量的前景。正文一一PDAC的5年总生存率（OS）仅为11%。化疗方案的最新进展改善了可切除PDAC的患者预后；然而，80%的患者被诊断为晚期，无法进行治疗性手术。过去十年来，吉西他滨和氟嚓嚏为基础的联合方案已成为转移性胰腺癌症患者护理化疗的标准方案，尽管mOS仍保持在大约1年。与其他类型肿瘤形成鲜
2、明对比的是，针对PDAC,使用靶向药物的多次大规模试验均未成功。然而，对PDAC的生物学和遗传学的进一步了解促使了新的靶向和基于免疫的疗法的出现，这些疗法可能在不久的将来适用于PDAC患者。研究者回顾了目前对PDAC分子特征和免疫治疗的理解，以开发靶向和基于免疫的疗法，并改善PDAc患者的预后。PDAC的靶向治疗方法识别关键致癌驱动因素可能产生新的治疗PDAC的方法。在本节中，研究者回顾了PDAC分子表征的研究进展以及针对潜在靶点的治疗策略。PDAC基因突变概览几项大规模的基因组研究已经对PDAC中的潜在驱动突变进行了梳理，从而实现了基因组指导的临床决策和治疗开发。对切除的PDAC肿瘤的早期二
3、代测序（NGS研究表明，KRAS、TP53、CDKN2A和SMAD4显示出最高的突变频率，90%以上的个体具有致癌KRAS突变。国际癌症基因组联合会（ICGC）证实了这些发现，并描述了几个结构变异。此外，癌症基因组图谱（TCGA）计划报告了20个基因的突变频率低于10%其中包括染色质修饰基因（如ARID1A、KMT2D和KMT2C）、DNA修复基因（如BRCA1、BRCA2和PALB2师其他癌基因（BRAFxMYC、FGFR1和其他）。在所有针对PDAC基因突变位点的研究中，局限性包括BRCA1、BRCA2或MSI-H以外的基因突变频率相对较低，以及对晚期疾病患者和通常表现不佳的患者进行临床试
4、验的可及性。最近出现了针对KRAS野生型和KRAS基因突变的治疗方法，对于KRAS突变的PDAC可能会在不久的将来受益于基因型靶向治疗。NTRKfusionsROS1fusions AtKfusionsRfusonsAMG,fusions 、RFmutations -MSI*Hstatus，Urotrectinfce.nt3eEntrectinibCrtzontinlb.centlnt). alCM)PraIseM)AtetintEncocafenibMnimenbnbRembrolizumabe图1.PDAC中KRAS靶向治疗演变PDAC中不同KRAS错义突变的相对频率。显示了针对指定KRA
5、S突变位点的研究性和FDA批准的精确治疗。表LPDAC精准治疗方法Table11PrecisionmedicineapproachesforPDACtherapyKRAStargetingsmall-moleculetherapeuticsinpreclinicaland/orclinicaldevelopmentforthetreatmentofPDACDrugTargetMechanismPhaseoftrialTrialdesignCancertypePrimaryoutcomePreclinicalreferenceClinicalreferenceSotorasib4(AMG-510
6、)KRAS61xSmall-moleculebindingofGDPboundStateofKRAScccIZHSequential,doseindigarmsWithdruggivenasamonotherapyandincombinationwithPD-IBaskettrialwithmultipletypesOfsolidtumorsenrolled(KRAS尔mutation-positive)Treatment-relatedadverseevents32,3336,37Adagrasib1(MRTX849)KRASWXSmall-moleculebindingofGDP-bodS
7、Uteo(KRAStwlSequential,dose-findingarmsWithdruggrvenasmonotherapyBaskettrialwithmultipletypesofsolidtumorsenrolled(KRAS6,xmutation-positive)Treatment-relatedadverseeventsandearlydinicalactivitysignal3841lSequentialdose-findingarmstestedincombinationwithSHP2inhibitor(TNO155)Baskettrialwithmultipletyp
8、esofsolidtumorsenrolled(KRAmutatipositive)Treatment-relatedadverseevents42MRTX1133cKRASgoSmall-moleculebindingofGOPandGTP-bondstatedKRAScuo*43PendingtrialregistrationRMC-629KRASwcTriconiplexinhibitor-46PendingtrialregistrationRMC6236,MuIti-RASTricomptexinhibrtor-BI1701963sPan-KRASSOSI-KRASinhibitorI
9、Two-armtrial:drugaloneanddrugplustrametinibBaskettrialwithKRASmutatedadvancedsolidtumorsMT(XoRRinextensioncohort4950ApprovedandexperimentalprecisionmedkineapproachesinPDACDrUHS)TirgetIndicationFrequencyofaberrationKRASWiidtypeormutantResponsesinPOAC-ReferencesPembrolizumabeMMR-dewithmsandPS3wildtype
10、4/22patientswithPOACwithobjectiveresponse-*13Z1412Xr211IarareCMMentrectinib4NTRK(genefusions)AdvcedsolidtumorwithNTRKgenefusionRareeventinPDAC(1%)KRASwildtypePR-8M&89.212Encorafenibb.brimepositiveadvancedPDACHighincidenceKRASwildtypeKftASwiIdtypeExcellentdurableresponses-92.213-215Gizotinib*,ceritin
11、br3ectnibfrALKALKgenerearranged0.16%ofallpatientswithPDAGarxJ13%ofindividuals50yearsoldKftASwiIdtypeThreeoffourindividualstreatedwithALKinhibitorhaddiseasecontrol93EntreCtin眇ROSIApprovedforROSIfusionNSClCbutcasereportevidenceinPDACRareeventinPDAC(1)KRASwiIdtypeOneindividualwithPDACwithminorresponse8
12、6TrastuzumaUderuxtecanfeHER2HR2oVereXPreSSingadvancedsolidtumor(non-gltricvnonbreast)Amplifiedin2%ofPDACcasesKRASc,2vOneindividualwithPDACtested(PR)-*21617Prilsetinib*(BLU-667)RETRfTfusionadvancedsolidtumors(threepatientswithPDAC)RareeventinPDAC(1)KRASwildtype(1.35%)andKRASmutant(0.22%)ResponseinMpa
13、tientswithPDACtested-74,91KRAStargetingsmall-moleculetherapeuticsinpredinicaland/orclinicaldevelopmentforthetreatmentofPDACDrugTargetMechanismPhaseoftrialTrialdesignCancertypePrimaryoutcomePreclinicalreferenceClinicalreferenceGinkaltrialsvaluatmsDNAdamager*spome-UrgtedthraputkagntsinPOACDrUg(*)Targe
14、tPopuUtionTrialstatmIrialdtsignPasoftrialPrimaryfindingsorendpointPiclinkalreferenceClinicalreferenceOlapvibPARPPatientswithBRCA)-or8RCA2nutatedmetastaticPDACCompleted(FDAapproved)TwoarvrandomizedPhMecontroltrialIIIPFS：PUParibsuperiortoPUceboasmaintenance99799RucaparibPARPPitientswithBRCAhBRCA2orRAL
15、2muta(edmetastaticPDACCompletedSinglmrmstudyIlPFS-rucaparibsuperiortoPUceboasmaintenance997101CiSPIM访,veiparibPARPandDNA(alkylation)PitientswithRCA),BRCA2orRALS2nuta(edmetastaticPDACCompleted(NCCNrecommendatio)TworvrandomizedcontroltrialIlPFSindOS:equivalentbetweenpatinufPARPinhibitorversusplatinuma
16、rms,andexcellentresponsewvtPUtinum99710303ibPARPPatientswith8ROU,BRCAorRAt2-muUtedPDACinthearrrandomizedcontroltrialIlPFS9971050lapMib.PefnbrOIumabPARPandPD-IPaticntswithBRCAI-or8RCA2-nuUtedmetastaticPDACRecruitingTwoarvrandomizedcontroltrialIlPFS106107Nrapanb.dosUrlwbPARPandPD-IPatientswithBRCAhBRC
17、A2orMlfiP-EutatedmetastaticPDACRecruitingSingle-armstudyIlDisedsecontrolrateM12months106108BAY1895344cATRMultiplesolidtumorsincludingPOACNotyetrecruitingTwo-arvnon-randomizdtrialITbkrabilrtyofagentwithORRasanexploratoryobjectiveno2AZD6738*folaparib ATRORRIH113MultiplesolidtumorsRecruiting1woarm,incl
18、udingPDACnon-randomizedtrialaTtsse-agnosticapprovalforindicatedtargettOff-UbeIuseinPDACMrwestigationaldrugATR.ataxiatelangiectasiaandRad3-relatedprotein;MMRmismatchrepair;MTD,maximumtolerateddose;NCCKNationalComprehensiveCancrNetworkORR.overallresponserate.图2.PDAC的免疫治疗方法a、PDAC的两种免疫治疗方法示意图：靶向免疫抑制性髓细胞
19、和重新编程DC和巨噬细胞,这两种策略都集中于提高CD8+淋巴细胞对PDAC癌症细胞的活性。对免疫抑制性髓系细胞粒细胞MDSCs（gMDSCs沐口m。MDSCS进行治疗干预的特异性受体分另（J为CXCR2和CCR2FLT3配体（FLT3L）促进从骨髓中募集cDC1z而激动性抗CD40单克隆抗体和CpG促进cDC1和杀瘤巨噬细胞活性。其他三种标记分子（聚肌苗酸-聚胞嚓咤酸和聚赖氨酸（聚ICLC）、Toll样受体7（TLR7）激动剂和脂质纳米颗粒疫苗）主要通过增加CDCIS的活性发挥潜在的抗PDAC抗体活性。b、PDAC肿瘤微环境的特点是细胞毒性T细胞浸润差以及由大量活化成纤维细胞、细胞外基质蛋白和
20、肿瘤-促进髓细胞组成的促结缔组织增生基质。通过几种研究方法对活化的成纤维细胞进行重新编程可能会减弱促结缔组织增生基质，并改善PDAC对于化疗和ICB治疗的敏感性。IL-1.IL-1;PIN1z肽基脯氨酰顺反异构酶NlMA相互作用1；TH1细胞、1型辅助T细胞。表2.在PDAC中正在进行的疫苗临床试验Table2SelectedvaccineclinicaltrialsinPDACVaccinecandidateMoleculartargetsMechanismPhaseoftrialTrialdesignPopulationPrimaryendpointsNumberofindividuals
21、ClmicaltrialreferencemRNA-567VV941KRAS6吗KRASvv.KRA可KRAS6vcERNAg4instKRASelicitsTcellresponse1lwontri4l:drugloneanddrugPiuSpembflccinPoIy-IClCTargetedlongpeptidevaccinelidtsimmunresponseagnstmutantKRAS1Sirearm.sequentialassignmentofindividualsIndividualsathhriskofdevelopingPDACbyfxniIyhistoryorgecmln
22、emutationstatusDrug-reiatedtoxcitieinterfntKRAS*speciicCD4andCD8Tcells25219KRASpepgensPOly-ICLCandpersonalizedmesothelinegensecifkCD4andCD8TCHresponsesS*ngle-anstudyofpatientswithPDACPatientswithPDACfOeoWingsurgicalresectionand(rantchemotherapySafetyofneoantigen15XPtidevacn221RO7198457(mRNA-bsedPtrs
23、onakredtumorvaccine)Iunxx-assooatedanticsAntigen-preentirgcellstakeupmRNAbasedvccinandexpresstuor-4Sociatedantigens,leadingtocytotoxandmemoryTcellimmuneresponsesag*instthetumor-associatedantigensSynthetkpersozdtumor-9S(ociatedpe(*devaccinether(yIumor-associatedantigensAntigenpresentifgcellstakeupmRN
24、AbasedYaCCiVWandexpresstumor-associatedAntigenIeadingtocytotoxicandmemoryTcellimmuneresponsesAgainstthetumor-associatedantigensSingle-armstudyinwicpatientswithPDACundergosurgicalresectionfollowedbyMezotojmdbtreatment,apersonalisedcancervaccineandfolfirinoxchemotherapySingle*armstudyinwicindividualsa
25、retreatedWithIrmquimod(TLR7agonist),PembrolizumabandVBCCinetherapyPatientswithPDACundergoingcurativeintentrMCtioPatientswithadvancedPDACandcoorecUcancerN/A.notappbcjbk.Safetyofa20personalizedtumorvaccinecombinedwithatez。IinJZbandFOLfIRINOXDemoftStfatefeasibility60ofcustomvaccine.Demomtratethtthecust
26、ompeptide-basedvaccineinComblndtk)nwithPembrolizumabissafe表3.PDAC中的免疫治疗试验Table31SelectedimmunotherapytrialsinPDACStrategyMoleculartargetCelltargetsPreclinkal/clinicalreferenceActiveclinicaltrial(s)Removingshort-livedCCR2InfiltratingmonocytkimmunosuppressiveCdIS158.224161immunosuppressivemyeloidcells
27、CXCR2Infiltratinggranulocyticimmunosuppressivecells156225ReprogrammingDCstobetterprimetumor-specificTcellresponsesFLT3LandCD40(agonism)FLT3LmobilizesconventionalDCfrombonemarrow.CD40agonismactrvateseDCswithinthetumormicroenvironment163.164165v166ReprogrammingPDAC-associatedfibroblastsVitaminDrecepto
28、rPDAC-assoctedfibroblasts226198,199BlockingimmunosuppressiveTGFsignalingAngiotensinIlreceptorPDAC-associatedfibroblasts197196BlockingimmunosuppressiveTGFsignalingTGFPDAC-associatedfibroblasts19Z194195BlockingimmunosuppressiveIL-1signalingIL-1PDAC-associatedfibroblasts189.205207在过去十年中，我们通过对人类样本和GEMs的深入分析，深入了解了PDAC中反复发生的驱动突变。正如最近成功批准PARP抑制剂和PD-1阻断剂用于PDAC的分子定义亚类，基于精确靶向和免疫疗法的方案开辟了新的治疗途径。KRAS特异性抑制剂的持续发展令人期待其在PDAC领域的研究突破。此外，了解PDAC中化疗耐药性的机制对于控制这种全身性疾病至关重要。最后，随着PDAC治疗有望取得进展，还需要关注旨在提高患者生活质量的措施，如癌症相关恶病质。我们预测，未来十年将有大量精确的肿瘤学方法来治疗这种顽固性癌症，这将使越来越多的患者受益。
