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免疫治療：卵巢癌治療福音

于金江綜述崔玉蘭審校

【關(guān)鍵詞】卵巢癌；免疫治療

卵巢癌是最致命的女性惡性疾病，當(dāng)前對(duì)于其治療仍局限于手術(shù)結(jié)合放療、化療等方法。這些方法只能清除部分實(shí)體腫瘤細(xì)胞，而對(duì)殘存及播散腫瘤細(xì)胞效果甚微。腫瘤免疫治療是目前公認(rèn)的、有望徹底消滅殘存癌細(xì)胞的生物治療方法[1]。本文將對(duì)近幾年關(guān)于卵巢癌免疫治療中研究較多的幾種方法作一闡述。

1被動(dòng)抗體治療

在過去的數(shù)年間，基于抗體療法在白血病及實(shí)體腫瘤治療中得到了完美闡釋。繼利妥昔單抗被美國(guó)食品與藥品監(jiān)督局(FDA)批準(zhǔn)可應(yīng)用于耐藥性非霍奇金淋巴瘤以來，越來越多的抗體被發(fā)現(xiàn)可用于卵巢癌治療。

1.1貝伐株單抗(bevacizumab avastin)貝伐株單抗是重組人源化抗血管內(nèi)皮生長(zhǎng)因子(VEGF)單抗。其通過抑制VEGF與相應(yīng)受體結(jié)合，影響腫瘤脈管回歸過程，從而延緩腫瘤進(jìn)展[2]。抗VEGF療法已被證明對(duì)非小細(xì)胞肺癌、膠質(zhì)細(xì)胞瘤等多種癌癥亞型都有效[3]，III期AURELIA試驗(yàn)證明給予鉑類耐藥卵巢癌患者治療，患者無進(jìn)展生存期(PFS)由3.4個(gè)月延長(zhǎng)到了6.7個(gè)月，總緩解率(OS)由11%提高到了27%[4]。對(duì)鉑敏感復(fù)發(fā)性卵巢癌OCEANS試驗(yàn)證明，貝伐株單抗可延長(zhǎng)患者FPS，而對(duì)OS無效[5]。

1.2西妥昔單抗和帕尼單抗(cetuximab and panitumumab)西妥昔單抗是一類針對(duì)表皮生長(zhǎng)因子受體(EGFR)的嵌合IgG1單抗，通過阻礙EGFR信號(hào)傳導(dǎo)通路并促進(jìn)受體內(nèi)化過程來發(fā)揮抗腫瘤作用[6]。西妥昔單抗起初用于治療轉(zhuǎn)移性結(jié)腸癌或頭頸部腫瘤，然而超70%卵巢腫瘤及所有卵巢癌亞型中EGFR陽(yáng)性，這預(yù)示著以EGFR為靶點(diǎn)的單抗可用于卵巢癌治療。在一項(xiàng)鉑劑聯(lián)合西妥昔單抗治療卵巢癌II期試驗(yàn)中也表現(xiàn)出可喜結(jié)果，29例患者中有客觀反應(yīng)者9例，8例病情得到維持[7]。帕尼單抗是一種具有極強(qiáng)抗EGFR抗體。在一項(xiàng)帕尼單抗聯(lián)合聚乙二醇脂質(zhì)體阿霉素化療治療鉑類耐藥卵巢癌II期試驗(yàn)報(bào)道中，9%患者達(dá)到部分緩解，19%病情得到穩(wěn)定[8]。

1.3曲妥珠單抗和帕妥珠單抗(trastuzumab and pertuzumab)曲妥珠單抗是一種靶向人類表皮生長(zhǎng)因子受體2(HER-2/neu)胞外結(jié)構(gòu)域并抑制其陽(yáng)性腫瘤細(xì)胞增殖的人源性單抗。在一項(xiàng)卵巢癌試驗(yàn)中，單藥曲妥株單抗表現(xiàn)出低免疫反應(yīng)性，無進(jìn)展期中位數(shù)僅為2個(gè)月[3]，在II期試驗(yàn)聯(lián)合紫杉醇及卡鉑治療7例耐紫杉醇/卡鉑及HER-2/neu過表達(dá)卵巢癌，結(jié)果表現(xiàn)出良好的臨床反應(yīng)性，3個(gè)患者中位PFS為2.9個(gè)月，OS為12.3個(gè)月[9]。帕妥株單抗作為HER抑制劑，發(fā)揮抑制腫瘤細(xì)胞生長(zhǎng)作用。單藥治療復(fù)發(fā)性卵巢癌期試驗(yàn)結(jié)果顯示，僅有4.3%患者表現(xiàn)出反應(yīng)性，6.8%患者病情平穩(wěn)達(dá)6個(gè)月[10]，在聯(lián)合吉西他濱治療鉑耐藥患者中，其反應(yīng)性升至13.8%[11]。

2免疫檢查點(diǎn)阻滯劑

免疫檢查點(diǎn)是一類抑制性分子，它主要通過抑制活化T細(xì)胞抗原提呈及協(xié)同共刺激信號(hào)，從而調(diào)節(jié)免疫反應(yīng)的強(qiáng)度及廣度，以避免自體組織損傷。而腫瘤細(xì)胞可表達(dá)免疫激活通路蛋白，抑制免疫，從而逃避免疫系統(tǒng)攻擊。

2.1程序性死亡受體1(PD-1)和配體(PD-L1)PD-1與PD-L1可以針對(duì)性地扭轉(zhuǎn)腫瘤介導(dǎo)的免疫抑制[12]。在一項(xiàng)小鼠細(xì)胞毒性試驗(yàn)中看到，在上皮卵巢癌ID8細(xì)胞中的PD-L1過表達(dá)，能夠抑制細(xì)胞毒性T細(xì)胞(cytotoxic lymphocyte，CTL)脫顆粒及減少CTL介導(dǎo)腫瘤裂解，而PD-L1阻斷恰好可逆轉(zhuǎn)這種局面[13]。有研究顯示，在卵巢癌患者血液及腹水單核細(xì)胞中的PD-L1表達(dá)量與不良預(yù)后有關(guān)[14]。

3過繼細(xì)胞治療(adoptive cell therapy,ACT)

4疫苗

疫苗是當(dāng)前研究最為活躍的治療藥物，其治療機(jī)制主要是通過啟動(dòng)癌患者自身免疫系統(tǒng)，增加腫瘤相關(guān)抗原(tumor-associated antigen, TAA)提呈，活化產(chǎn)生記憶性CTL，以達(dá)清除腫瘤細(xì)胞的目的。

4.1樹突狀細(xì)胞(dendritic cell，DC)疫苗DC是最有潛能的抗原提成細(xì)胞(antigen presenting cell，APC)，負(fù)責(zé)提呈癌細(xì)胞抗原及肽片段給T/B淋巴細(xì)胞及NK細(xì)胞。DC疫苗主要是通過加強(qiáng)DC攝取及TAA提呈作用來實(shí)現(xiàn)抗腫瘤作用。研究發(fā)現(xiàn)，糖基化跨膜蛋白-1(MUC-1)高表達(dá)于卵巢癌中[24]。MUC-1自體樹突狀細(xì)胞治療(CVAV)在上皮卵巢癌II期治療CAN-003研究表明，治療后第2次完全緩解(CR)63例，CR緩解率為33.3%，PFS得到了顯著改善[25]。早期關(guān)于卵巢癌臨床有效的案例還有間皮素—人熱應(yīng)激蛋白70(MSLN-Hsp70)的應(yīng)用[26]。

4.4重組病毒疫苗重組基因疫苗是利用轉(zhuǎn)基因病毒作為載體將TAA編碼DNA導(dǎo)入人體細(xì)胞中。病毒作為抗原運(yùn)載系統(tǒng)，其免疫原性誘發(fā)免疫細(xì)胞募集到APC與新引入的TAA相遇的地方，然后APC進(jìn)入到吸收和表達(dá)TAA的淋巴結(jié)，從而誘導(dǎo)腫瘤特異性細(xì)胞或體液免疫[31]。腫瘤睪丸抗原NY-ESO-1是目前有證可循的靶向治療卵巢癌及多種癌癥的疫苗。重組NY-ESO-1疫苗和雞痘病毒載體被用作II期臨床試驗(yàn)，得到了出人意料的可喜結(jié)果[32]。PANVAC作為癌癥疫苗可刺激免疫系統(tǒng)表達(dá)癌胚抗原(CEA)及MUC-1，并被稱作共刺激分子三聯(lián)體IRICOM(B7.1/ICAM-1/LFA-3)[33]。在一項(xiàng)PANVAC治療卵巢癌研究中顯示，疾病進(jìn)展時(shí)間中位數(shù)為2個(gè)月，中位OS為15個(gè)月[34]。

5腫瘤免疫基因療法

6展望

卵巢癌是常見的婦科腫瘤，由于缺乏敏感、特異的早期診斷方法，病死率一直徘徊在45%左右。近幾年隨著免疫基礎(chǔ)理論的的發(fā)展，為卵巢癌臨床治療帶來了無限生機(jī)。然而，在治療中也發(fā)現(xiàn)了其中不足，即在治療中如何把握度、如何避免免疫微環(huán)境的抑制作用、如何抑制免疫逃逸機(jī)制等問題，值得我們?nèi)ニ伎肌，F(xiàn)階段，以免疫療法為載體聯(lián)合光動(dòng)力學(xué)治療、納米載藥系統(tǒng)治療、輻射治療、干細(xì)胞治療以及中醫(yī)中藥治療卵巢癌的綜合策略也在進(jìn)一步試驗(yàn)中,相信隨研究的進(jìn)一步深入，聯(lián)合治療克服卵巢癌及其他癌癥指日可待。

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綜述

收稿日期：(2015-04-20)

【DOI】10.3969 / j.issn.1671-6450.2015.12.032

作者單位： 150086哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院婦產(chǎn)科