免疫治療：卵巢癌治療福音

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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

【關鍵詞】卵巢癌；免疫治療

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

1被動抗體治療

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

1.1貝伐株單抗(bevacizumab avastin)貝伐株單抗是重組人源化抗血管內皮生長因子(VEGF)單抗。其通過抑制VEGF與相應受體結合，影響腫瘤脈管回歸過程，從而延緩腫瘤進展[2]。抗VEGF療法已被證明對非小細胞肺癌、膠質細胞瘤等多種癌癥亞型都有效[3]，III期AURELIA試驗證明給予鉑類耐藥卵巢癌患者治療，患者無進展生存期(PFS)由3.4個月延長到了6.7個月，總緩解率(OS)由11%提高到了27%[4]。對鉑敏感復發性卵巢癌OCEANS試驗證明，貝伐株單抗可延長患者FPS，而對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表皮生長因子受體(EGFR)的嵌合IgG1單抗，通過阻礙EGFR信號傳導通路并促進受體內化過程來發揮抗腫瘤作用[6]。西妥昔單抗起初用于治療轉移性結腸癌或頭頸部腫瘤，然而超70%卵巢腫瘤及所有卵巢癌亞型中EGFR陽性，這預示著以EGFR為靶點的單抗可用于卵巢癌治療。在一項鉑劑聯合西妥昔單抗治療卵巢癌II期試驗中也表現出可喜結果，29例患者中有客觀反應者9例，8例病情得到維持[7]。帕尼單抗是一種具有極強抗EGFR抗體。在一項帕尼單抗聯合聚乙二醇脂質體阿霉素化療治療鉑類耐藥卵巢癌II期試驗報道中，9%患者達到部分緩解，19%病情得到穩定[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因子受體2(HER-2/neu)胞外結構域并抑制其陽性腫瘤細胞增殖的人源性單抗。在一項卵巢癌試驗中，單藥曲妥株單抗表現出低免疫反應性，無進展期中位數僅為2個月[3]，在II期試驗聯合紫杉醇及卡鉑治療7例耐紫杉醇/卡鉑及HER-2/neu過表達卵巢癌，結果表現出良好的臨床反應性，3個患者中位PFS為2.9個月，OS為12.3個月[9]。帕妥株單抗作為HER抑制劑，發揮抑制腫瘤細胞生長作用。單藥治療復發性卵巢癌期試驗結果顯示，僅有4.3%患者表現出反應性，6.8%患者病情平穩達6個月[10]，在聯合吉西他濱治療鉑耐藥患者中，其反應性升至13.8%[11]。

2免疫檢查點阻滯劑

免疫檢查點是一類抑制性分子，它主要通過抑制活化T細胞抗原提呈及協同共刺激信號，從而調節免疫反應的強度及廣度，以避免自體組織損傷。而腫瘤細胞可表達免疫激活通路蛋白，抑制免疫，從而逃避免疫系統攻擊。

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

3過繼細胞治療(adoptive cell therapy,ACT)

4疫苗

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

4.1樹突狀細胞(dendritic cell，DC)疫苗DC是最有潛能的抗原提成細胞(antigen presenting cell，APC)，負責提呈癌細胞抗原及肽片段給T/B淋巴細胞及NK細胞。DC疫苗主要是通過加強DC攝取及TAA提呈作用來實現抗腫瘤作用。研究發現，糖基化跨膜蛋白-1(MUC-1)高表達于卵巢癌中[24]。MUC-1自體樹突狀細胞治療(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]。早期關于卵巢癌臨床有效的案例還有間皮素—人熱應激蛋白70(MSLN-Hsp70)的應用[26]。

4.4重組病毒疫苗重組基因疫苗是利用轉基因病毒作為載體將TAA編碼DNA導入人體細胞中。病毒作為抗原運載系統，其免疫原性誘發免疫細胞募集到APC與新引入的TAA相遇的地方，然后APC進入到吸收和表達TAA的淋巴結，從而誘導腫瘤特異性細胞或體液免疫[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，得到了出人意料的可喜結果[32]。PANVAC作為癌癥疫苗可刺激免疫系統表達癌胚抗原(CEA)及MUC-1，并被稱作共刺激分子三聯體IRICOM(B7.1/ICAM-1/LFA-3)[33]。在一項PANVAC治療卵巢癌研究中顯示，疾病進展時間中位數為2個月，中位OS為15個月[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理論的的發展，為卵巢癌臨床治療帶來了無限生機。然而，在治療中也發現了其中不足，即在治療中如何把握度、如何避免免疫微環境的抑制作用、如何抑制免疫逃逸機制等問題，值得我們去思考。現階段，以免疫療法為載體聯合光動力學治療、納米載藥系統治療、輻射治療、干細胞治療以及中醫中藥治療卵巢癌的綜合策略也在進一步試驗中,相信隨研究的進一步深入，聯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哈爾濱醫科大學附屬第二醫院婦產科