乳腺癌晚期患者的免疫治療研究進(jìn)展

乳腺癌晚期患者的免疫治療研究進(jìn)展[摘要]生物免疫療法是利用生物制劑和生物技術(shù)對(duì)患者體內(nèi)采集的免疫細(xì)胞進(jìn)CIK免疫療法、MDX-H210免疫療法、腫瘤疫苗免疫療法、DC免疫療法和EGFR免疫療法，生物免疫療法有效克服了傳統(tǒng)手術(shù)、放療和化療三大治療方式一世紀(jì)腫瘤綜合治療模式中不可缺少的-種治療手段。[關(guān)鍵詞]乳腺癌，免疫治療，免疫功能，自身免疫[1-2]，近幾年來乳腺癌的臨床發(fā)病率在全球范圍內(nèi)呈逐[3]。但手術(shù)治療后的創(chuàng)傷不易恢復(fù);放療在殺滅腫瘤組織的同時(shí)對(duì)患者的免疫及造血系統(tǒng)造成了嚴(yán)重的傷害;化療本身就有毒副作用[4]效滿意和不良反應(yīng)低的特點(diǎn)，現(xiàn)綜述如下：免疫治療乳腺癌概況生物免疫治療方法在臨床上主要是指利用生物制劑和生物技術(shù)對(duì)患者體內(nèi)增強(qiáng)機(jī)體自身免疫功能的目的[5-6]。其臨床應(yīng)用的主要優(yōu)勢(shì)在于：在手術(shù)治療后[8]。免疫療法研究進(jìn)展隨著細(xì)胞生物學(xué)、分子生物學(xué)和免疫學(xué)技術(shù)的快速發(fā)展，生物免疫技術(shù)逐漸[9-10]CIKMDX-H210DCEGFR免疫療法，現(xiàn)分別綜述如下。CIK免疫療法治療乳腺癌概況多種細(xì)胞因子誘導(dǎo)的殺傷細(xì)胞(CIK)屬于人體免疫細(xì)胞中的-種，可以由多種細(xì)胞因子誘導(dǎo)產(chǎn)生，不但具有T淋巴細(xì)胞的抗癌功能，還具有NK細(xì)胞的MHC限制性抑癌能力，現(xiàn)已在多種惡性腫瘤（乳腺癌、腸癌和胃癌等）的免疫治療中得到廣泛應(yīng)用[11]。多種細(xì)胞因子誘導(dǎo)的殺傷細(xì)胞主要包括 CD3+CD56+和CD3+CD8+的T細(xì)胞其抗癌活性明顯高于淋巴因子激活的殺傷細(xì)胞(LAKWeiLiu,MingxiaZhai,ZongyinWuet al在文獻(xiàn)研究中[12]對(duì)46例老年晚期乳腺癌患者進(jìn)行研究，觀察組患者經(jīng)過常規(guī)化療+CIK方法治療后，臨床有效率達(dá)到73.9％，明顯高于對(duì)照組療效結(jié)果（P<0.05，另外，觀察組患者在治療后，其體內(nèi)的總T淋巴細(xì)胞(CD3+)、T輔助細(xì)胞(CD3+／CD4+)、T抑制細(xì)胞(CD3+／CD8+)和NK 細(xì)胞(CD3-／CDl6+CD56+)水平也明顯優(yōu)于對(duì)照組統(tǒng)計(jì)結(jié)果P<0.05CIK疫功能，而且不會(huì)產(chǎn)生明顯的毒性反應(yīng)，值得在臨床上推廣應(yīng)用。MDX-H210免疫療法治療乳腺癌概況包括兩個(gè)能夠和不同的抗原決定簇發(fā)生特異性結(jié)合的單克隆抗體片段，不但能夠與腫瘤細(xì)胞相關(guān)抗原(HER-2)還能夠與血液循環(huán)中具有免疫效應(yīng)細(xì)胞的受體（FcgammaRI(CD64)FcgammaRⅢ(CDl6)等）[13]進(jìn)行選擇性識(shí)別，還能將人體血液循環(huán)中的免疫效應(yīng)細(xì)胞(例如巨噬細(xì)胞、單核)et的文獻(xiàn)研究中[14]在G-CSF治療的基礎(chǔ)MDX-H210HER-2／neu高表達(dá)的Ⅳ期乳腺癌（晚期乳腺癌中的-種）患者進(jìn)行治療，在治療過程中，患者只表現(xiàn)出微弱的寒戰(zhàn)、發(fā)熱MDX-H210（1mgmlFegammaR度超過50％，沒有發(fā)現(xiàn)對(duì)正常組織的毒副作用。另外，研究中還通過免疫組化TNF-α、IL-6、G-CSF果都顯示了G-CSF與MXD-H210用效果。腫瘤疫苗免疫療法治療乳腺癌概況[15]。雖然很多的疫苗還處于臨床試驗(yàn)階段，但腫瘤疫苗免疫療法已被認(rèn)為是治療乳腺癌的理想手段，目前大約有超過-千種的腫瘤抗原獲得成功分離，其中不乏對(duì)乳腺癌的特異性抗原，相關(guān)臨床試驗(yàn)結(jié)果顯示[16]30Her-2/neu27er-2/neuT25例（83.3%）Her-2／neuIgG患者在治療過程中沒有出現(xiàn)明顯的不良反應(yīng)。DC免疫療法治療乳腺癌概況樹突狀細(xì)胞(DC)在臨床上是目前已知的具有最強(qiáng)功能的專職抗原提呈細(xì)胞相關(guān)文獻(xiàn)研究[17]表明DC在啟動(dòng)細(xì)胞免疫中發(fā)揮著關(guān)鍵性的作用最近幾年有學(xué)者[18]應(yīng)用GM—CSF聯(lián)合IL4等細(xì)胞因子從患者外周血單核細(xì)胞中對(duì)DC進(jìn)行誘導(dǎo)和擴(kuò)增，繼而利用人工合成的腫瘤相關(guān)抗原沖擊DC，或者通過基因轉(zhuǎn)染和瘤細(xì)胞雜交等方法讓DC 加載抗原，將其轉(zhuǎn)化為為DC 疫苗。Lekka,E.,Gritzapis,A.D.,Perez,S.A.etal在文獻(xiàn)研究中[19]用多肽體外沖擊致敏DC，再重新輸入到經(jīng)過化療的晚期乳腺癌患者體內(nèi)，取得了滿意的臨床效果。EGFR免疫療法治療乳腺癌概況酪氨酸激酶抑制劑能夠?qū)GFR胞內(nèi)酪氨酸激酶結(jié)構(gòu)域的自身磷酸化產(chǎn)生EGFR[20]，酪氨酸激酶抑制劑對(duì)多種EGFR過度表達(dá)的惡性腫瘤患者（包括晚期乳腺癌患者和胃癌患者等）的臨床效果。另有，一項(xiàng)關(guān)于IressaHer-2過度表達(dá)的轉(zhuǎn)移性乳EGFR的酪氨Her.2的信號(hào)轉(zhuǎn)導(dǎo)，從而提高赫賽汀的療效，即使對(duì)赫賽汀耐藥的轉(zhuǎn)移性乳腺癌仍有效?？偨Y(jié)與展望（-腫瘤綜合治療模式中不可缺少的-種治療手段。參考文獻(xiàn)ShihYC,EltingLS,PavluckAetal.Immunotherapyintheinitialtreatmentofnewlydiagnosedcancerpatients:utilizationtrendandcostprojectionsnon-Hodgkin'slymphoma,metastaticbreastcancer,andmetastaticcolorectalcancer.[J].Cancerinvestigation,2010,28(1):46-53.Buskas,T,Thompson,P,Boons,GJetal.Immunotherapyforcancer:syntheticcarbohydrate-basedvaccines[J].Chemicalcommunications,2009,2009(36):5335-5349.[3]Kiyamova,R.,Kostianets,O.,Malyuchik,S.etal.Identificationoftumor-associatedantigensfrommedullarybreastcarcinomabyamodifiedSEREXapproach[J].Molecularbiotechnology,2010,46(2):105-112.Tchou,J.,Wang,L.-C.,Selven,B.etal.Mesothelin,anovelimmunotherapytargetfortriplenegativebreastcancer[J].Breastcancerresearchtreatment,2012,133(2):799-804.Riccio,G.,D'avino,C.,Raines,R.T.etal.AnovelfullyhumanantitumorImmunoRNaseresistanttotheRNaseinhibitor[J].Proteinengineeringdesign&amp;selection,2013,26(3/4):243-248.Yan,H.-X.,Cheng,P.,Wei,H.-.etal.Activeimmunotherapyformousebreastcancerwithirradiatedwhole-cellvaccineexpressingVEGFR2[J].Oncologyreports,2013,29(4):1510-1516.Emens,L.A..Re-purposing cancer therapeutics for breast immunotherapy[J].CancerImmunologyandImmunotherapy,2012,61(8):1299-1305.[8]XiufenZheng,JamesKoropatnick,DiChenetal.SilencingIDOindendriticcells:Anovel approach to enhance cancer immunotherapy in a murine breast cancermodel[J].InternationalJournalofCancer=,2013,132(4):967-977.[9]Ascierto,M.L.,Kmieciak,M.,Idowu,M.O.etal.Asignatureofimmunefunctiongenesassociatedwithrecurrence-freesurvivalinbreastcancerpatients[J].Breastcancerresearchandtreatment,2012,131(3):871-880.Wood,L.M.,Pan,Z.-K.,Seavey,M.M.etal.Theubiquitin-likeprotein,ISG15,isanoveltumor-associatedantigenforcancerimmunotherapy[J].CancerImmunologyandImmunotherapy,2012,61(5):689-700.etal.Invitrosynthesisofprimaryspecificanti-breastcancerantibodiesbynormalhumanperipheralbloodmononuclearcells[J].CancerImmunologyandImmunotherapy,2011,60(12):1707-1720.WeiLiu,MingxiaZhai,ZongyinWuetal.IdentificationofanovelHLA-A2-restrictedcytotoxicTlymphocyteepitopefromcancer-testisantigeninbreastcancer[J].Aminoacids,2012,42(6):2257-2265.etal.ImmunotherapyforSV40T/tantigen-inducedbreastcancerbyrecombinantadeno-associatedvirusserotype2carryinginterleukin-15inmice[J].Internationaljournalofmolecularmedicine,2012,29(5):809-814.Mittendorf,E.A.,Clifton,G.T.,Holmes,J.P.etal.ClinicaltrialresultsoftheHER-2/neu(E75)vaccinetopreventbreastcancerrecurrenceinhigh-riskpatients:FromUSMilitaryCancerInstituteClinicalTrialsGroupStudyI-01I-02[J].Cancer,2012,118(10):2594-2602.etal.Autologousdendriticcellvaccineforestrogenreceptor (ER)/ progestin receptor (PR) double-negative breast ImmunologyandImmunotherapy,2012,61(9):1415-1424.[16]AnovelBacillusCalmette-Guerin-basedbreastcancervaccinethatcoexpressesmultipletandemrepeatsofMUC1andCD80breakstheimmunetoleranceandinhibitsMUC1-positivebreastcancergrowth.[J].Cancerbiotherapyradiopharmaceuticals,2009,24(5):607-613.Podnos,A.,Clark,D.A.,Erin,N.etal.Furtherevidenceforaroleoftumorexpressioninbreastcancermetastasis:DecreasedmetastasisinCD200R1KOmiceorusing CD200-silenced EMT6[J].Breast cancer research treatment,2012,136(1):117-127.Mandl,S.J.,Rountree,R.B.,Dalpozzo,K. et al.Immunotherapy ?-HER2inducesHER-2-specificTh1immunityandalterstheintratumoralbalance of effector and regulatory T cells[J].Cancer Immunology Immunotherapy,2012,61(1):19-29.Lekka,E.,Gritzapis,A.D.,Perez,S.A.etal.Identificationandcharacterizationof