再下一城！诺华-宾大即将开展CAR-T治疗恶性胶质瘤临床研究

2015年2月21日讯/生物谷BIOON/--如果要问2014年生物医药行业取得的重大突破有哪些，那么CAR-T疗法必定榜上有名。这种免疫疗法首先是通过分离患者体内的T细胞并在体外进行特定肿瘤抗体的修饰，经过扩增后再回输至患者体内。这种经过修饰的T细胞能够特异、高效的识别肿瘤细胞，从而达到在治疗肿瘤的同时又避免对正常组织的损伤。此前的CAR-T疗法一般都是以治疗白血病等肿瘤为主要靶点。
最近来自宾州大学和诺华公司的研究人员进行了一系列的动物实验证实了CAR-T疗法有希望用于治疗恶性胶质瘤。这种恶性脑瘤一直都是肿瘤疗法开发中的一大难点。每年美国有约2万2千人被诊断为患有这种癌症。由于发病部位在脑部，许多患者都无法及早诊断。目前治疗癌症的一些标准疗法都难以起到良好疗效，大多数患者确诊后生存期不到18个月。
根据参与这一项目的MarcelaMaus介绍，CAR-T疗法治疗恶性胶质瘤的一个困难就是如何寻找到一个合适的靶点。经过严格筛选，科学家们最终选择了一种名为EGFRvIII的表皮生长因子受体作为靶点。研究显示，在30%的恶性胶质瘤患者体内，肿瘤细胞表面都表达这种受体蛋白的突变体。更重要的是，表达这种突变体基因的肿瘤恶性程度更高。
基于这一原理，研究人员分离纯化了针对EGFRvIII突变体的抗体片段，并将其与T细胞进行偶联。科学家通过细胞实验和小鼠实验确定了这种抗体不会对正常的EGFRvIII产生作用以验证其安全性。随后研究人员在恶性胶质瘤小鼠模型上检测了CAR-T细胞疗法的抗肿瘤作用。通过磁共振成像等手段，科学家发现小鼠脑部的肿瘤出现萎缩的现象，当这种疗法和化疗药物替莫唑胺联用时，一些小鼠脑部的肿瘤甚至消失。大感振奋的研究人员随后根据这些数据设计出了一个小型的临床一期研究方案。科学家计划招募12名恶性胶质瘤患者，其中六人是接受过其他疗法治疗但未能收获理想疗效的患者，另外六人是刚刚确诊为恶性胶质瘤的患者。
而此次研究的赞助者为国际著名制药巨头诺华公司。CAR-T疗法的兴起使得宾州大学和诺华喜结连理。双方围绕着肿瘤免疫疗法达成了一系列长期的研究合作协议。也正由于这种产学研优势互补，使得诺华公司自免疫疗法兴起以来，就一直走在市场的最前列。
详细英文报道：
PreclinicalStudyResultsPavetheWayforNewlyOpenedClinicalTrialofImmuneCellsEngineeredtoAttackProteinFoundonTumorsin30PercentofPatientswithGlioblastoma
PHILADELPHIA-Immunecellsengineeredtoseekoutandattackatypeofdeadlybraincancerwerefoundtobebothsafeandeffectiveatcontrollingtumorgrowthinmicethatweretreatedwiththesemodifiedcells,accordingtoastudypublishedinScienceTranslationalMedicinebyateamfromthePerelmanSchoolofMedicineattheUniversityofPennsylvaniaandtheNovartisInstitutesforBioMedicalResearch.TheresultspavedthewayforanewlyopenedclinicaltrialforglioblastomapatientsatPenn.
"AseriesofPenntrialsthatbeganin2010havefoundthatengineeredTcellshaveaneffectintreatingsomebloodcancers,butexpandingthisapproachintosolidtumorshasposedchallenges,"saidthestudysseniorauthor,MarcelaMaus,MD,PhD,anassistantprofessorofHematology/OncologyinPennsAbramsonCancerCenter."AchallengingaspectofapplyingengineeredTcelltechnologyisfindingthebesttargetsthatarefoundontumorsbutnotnormaltissues.ThisisthekeytomakingthiskindofTcelltherapybotheffectiveandsafe."
Thenewpreclinicalstudy,conductedincollaborationwithHidehoOkada,MD,PhDandhiscolleaguesattheUniversityofPittsburgh,detailsthedesignanduseofTcellsengineeredtoexpressachimericantigenreceptor(CAR)thattargetsamutationintheepidermalgrowthfactorreceptorproteincalledEGFRvIII,whichisfoundonabout30percentofglioblastomapatientstumorcells.Morethan22,000Americansarediagnosedwithglioblastomaeachyear.PatientswhosetumorsexpresstheEGFRvIIImutationtendtohavemoreaggressiveglioblastomas.Theirtumorsarelesslikelytorespondfavorablytostandardtherapiesandmorelikelytorecurfollowingthosetreatments.
"Patientswiththistypeofbraincancerhaveaverypoorprognosis.Manysurvivelessthan18monthsfollowingtheirdiagnosis,"saidM.SeanGrady,MD,theCharlesHarrisonFrazierProfessorandchairofthedepartmentofNeurosurgery."Wevebroughttogetherexpertsinanarrayoffieldstodevelopaninnovativepersonalizedimmunotherapyforcertainbraincancers."
ThenewtrialisledbyDonaldM.ORourke,MD,anassociateprofessorofNeurosurgery,whooverseesaninterdisciplinarycollaborationofneurosurgeons,neuro-oncologists,neuropathologists,immunologists,andtransfusionmedicineexperts.
Mausdescribesthegenesisofthenewresultsasa"tourdeforce,"intermsoftherangeofexperimentsperformedtocharacterizetheEGFRvIIICARTcell.First,theteamdevelopedandtestedmultipleantibodies,orwhatimmunologistscallsingle-chainvariablefragments(scFv),whichbindtocellsexpressingEGFRvIIIontheirsurface.ThescFvsrecognizingthemutatedEGFRvIIIproteinmustberigorouslytestedtoconfirmthattheydonotalsobindtonormal,non-mutatedEGFRproteins,whicharewidelyexpressedoncellsinthehumanbody.
TheresearchersthengeneratedapanelofhumanizedscFvsandtestedtheirspecificityandfunctioninCARmodifiedTcells.(HumanizedscFvsaremolecularlychangedfromtheiroriginsinnon-humanspeciestoincreasetheirsimilaritytohumanantibodies.)OutofthepanelofhumanizedscFvsthatweretested,theresearchersselectedonescFvtoexplorefurtherbasedonitsbindingselectivityforEGFRvIIIovernormalnon-mutatedEGFR.TheyalsoevaluatedtheEGFRvIIICARTcellsinanassayutilizingnormalEGFR-expressingskincellsinmicegraftedwithhumanskin.TheyfoundthattheengineeredEGFRvIIICARTcellsdidnotattackcellswithnormalEGFRinthismodel.
TheleadscFvwasthentestedforitsanti-cancerefficacy.Usinghumantumorcells,thescientificteamdeterminedthattheEGFRvIIICARTcellscouldmultiplyandsecretecytokinesinresponsetotumorcellsbearingtheEGFRvIIIprotein.Importantly,theresearchersfoundthattheEGFRvIIICARTcellscontrolledtumorgrowthinseveralmousemodelsofglioblastoma,asmeasuredbymagneticresonanceimaging(MRI)andluminescenceoftumorsinthemousebrains.Inthemousemodel,theEGFRvIIICARTcellscausedtumorshrinkagewhenmeasuredbyMRIandwerealsoeffectiveineliminatingtumorswhenadministeredincombinationwithtemozolomidechemotherapythatisusedtotreatpatientswithglioblastoma.
Onthebasisofthesepreclinicalresults,theinvestigatorsdesignedaphase1clinicalstudyofCARTcellstransducedwithhumanizedscFvdirectedtoEGFRvIIIforbothnewlydiagnosedandrecurrentglioblastomapatientscarryingtheEGFRvIIImutation."Thereareuniqueaspectsabouttheimmunesystemthatwerenowabletoutilizetostudyacompletelynewtypeoftherapy,"saidORourke.
TheinvestigationalapproachbeginswhensomeofeachpatientsTcellsareremovedviaanapheresisprocesssimilartodialysis,thecellsareengineeredusingaviralvectorthatprogramsthemtofindcancercellsthatexpressEGFRvIII.Then,thepatientsownengineeredcellsareinfusedbackintotheirbody,whereasignalingdomainbuiltintotheCARpromotesproliferationofthese"hunter"T-cells.IncontrasttocertainTcelltherapiesthatalsotargetsomehealthycells,EGFRvIIIisbelievedtobefoundonlyontumortissue,whichthestudysleadershopewillminimizesideeffects.
Thenewtrialwillenroll12adultpatientswhosetumorsexpressEGFRvIII,intwogroups:Onearmof6patientswhosecancershavereturnedafterreceivingothertherapies,andonearmof6patientswhoarenewlydiagnosedwiththediseaseandstillhave1cmormoreoftumortissueremainingafterundergoingsurgerytoremoveit.
TheclinicaltrialissponsoredbyNovartis.In2012,theUniversityofPennsylvaniaandNovartisannouncedanexclusiveglobalresearchandlicensingagreementtofurtherstudyandcommercializenovelcellularimmunotherapiesusingCARtechnologies.TheSTMstudyisthefirstpre-clinicalpaperdevelopedwithinthePenn-Novartisalliance,withPennandNovartisscientistsworkingcollaboratively.OngoingclinicaltrialsevaluatingadifferenttypeofPenn-developedCARtherapyknownasCTL019haveyieldedpromisingresultsamongsomepatientswithcertainbloodcancers.InJuly2014,theFDAgrantedCTL019itsBreakthroughTherapydesignationforthetreatmentofrelapsedandrefractoryacutelymphoblasticleukemiainbothchildrenandadults.Formoreinformationabouttheglioblastomatrial,visitclinicaltrials.gov.
ThisSTMstudywassupportedbyfundingfromtheNationalInstitutesofHealth(DP2CA174502),theNationalCancerInstitute(K08-166039),anAmericanSocietyofClinicalOncologyConquerCancerFoundationYoungInvestigatorAward,andtheNovartisInstitutesforBioMedicalResearchaspartofanalliancewiththeUniversityofPennsylvania.

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