腫瘤樹突狀細胞疫苗研究進展

汪 英,李錫春

(1.四川省人民醫(yī)院城東病區(qū),四川成都610101;2.中航工業(yè)成飛醫(yī)院,四川成都610092)

腫瘤樹突狀細胞疫苗研究進展

汪 英1,李錫春2

(1.四川省人民醫(yī)院城東病區(qū),四川成都610101;2.中航工業(yè)成飛醫(yī)院,四川成都610092)

腫瘤免疫療法在過去的十年被臨床腫瘤學界視為一種越來越有效的治療模式。近年來,對腫瘤疫苗中的樹突狀細胞疫苗進行了大量的研究。對腫瘤樹突狀細胞疫苗研究進展進行簡述,目的是為讀者梳理出腫瘤疫苗的發(fā)展脈絡。

腫瘤;疫苗;樹突狀細胞

隨著腫瘤生物學和免疫學的發(fā)展,腫瘤免疫治療得到了迅速的發(fā)展。腫瘤免疫療法在過去的十年被臨床腫瘤學界視為一種越來越有效的治療模式。FDA即批準了兩個以免疫治療為基礎的產(chǎn)品,一個為治療前列腺癌的Provenge(sipuleuce-T)疫苗,另一個為治療黑色素瘤的抗細胞毒性T淋巴細胞相關抗原4(CTLA-4)的抗體ipilimumab疫苗。

腫瘤疫苗是指可以誘導機體產(chǎn)生針對腫瘤的特異性T細胞反應(包括CD8+和CD4+T細胞),以抑制或消除腫瘤生長、復發(fā)或轉(zhuǎn)移的各種形式的疫苗。由于方法不同,可出現(xiàn)很多的腫瘤疫苗分類。目前比較公認的分類方法是依據(jù)腫瘤疫苗的來源、作用對象及構(gòu)建載體來進行分類。通常腫瘤疫苗類型包括腫瘤細胞疫苗、基因工程疫苗、樹突狀細胞疫苗、病毒疫苗、多肽疫苗、核酸疫苗、抗獨特性抗體疫苗等。1996年美國斯坦福大學醫(yī)學中心Hsu等[1]在Nature Medicine上報道了全球首項樹突狀細胞(dendritic cell,DC)腫瘤疫苗臨床研究,4例濾泡性B淋巴細胞腫瘤患者接受腫瘤抗原刺激的自體外周血來源DC細胞治療,試驗結(jié)果令人鼓舞。一項Meta分析表明,接受DC疫苗治療的前列腺癌和腎細胞癌患者的目標應答率分別為7.7%和12.7%,臨床受益率分別為54%和48%,總緩解率分別為10.6%和8.4%?，F(xiàn)就腫瘤樹突狀細胞疫苗及其研究進展簡述如下。

1973年,Steinman和Cohn發(fā)現(xiàn)具有樹枝狀突起的獨特形態(tài)細胞,并將之命名為樹突狀細胞。DC參與多種疾病如感染、腫瘤、過敏及移植排斥的發(fā)生與發(fā)展。由于發(fā)現(xiàn)DC及其在獲得性免疫應答中的作用,Steinman榮獲2011年諾貝爾生理或醫(yī)學獎并被譽為DC之父[2-3]。隨著腫瘤免疫學的發(fā)展,DC作為腫瘤治療手段受到了越來越多的關注并被寄予厚望。負載腫瘤抗原的DC疫苗被認為是最具潛能的一種腫瘤免疫治療手段[4-5]。關于DC疫苗的研究主要有以下幾方面。

1 腫瘤抗原肽致敏DC疫苗

腫瘤抗原肽致敏DC具有很好的靶向性,試驗證明,在體內(nèi)、外均能誘導MHC-1和MHC-2的特異性T細胞反應。在體外,單獨的抗原肽則會引起特異性的CTL的耐受,而抗原肽致敏DC后能誘導針對腫瘤細胞的抗原特異性T細胞反應[4]。經(jīng)DC呈遞的人類或者小鼠的腫瘤抗原/肽能引起顯著性的抗腫瘤免疫反應。特別是MHC限制性合成腫瘤相關肽,如黑色素瘤相關抗原,內(nèi)源性逆轉(zhuǎn)錄病毒基因產(chǎn)品gp70/p15E,癌胚抗原(CEA),葉酸連接蛋白(FBP),前列腺特異性膜抗原(PMSA),survivin,MUC-1, HER2/neu和抗獨特性衍生的蛋白質(zhì)合成肽, bcr-ɑbl b3a2融合蛋白(ATGFKQSSKALQRPVAS)和一種合成的HPV16E7肽。腫瘤抗原肽致敏DC已在動物研究和臨床試驗中取得不同程度的效果[5-8]。與黑色素瘤相關的抗原gp100、MART-1、NA17及MAGE家族;與前列腺癌相關的抗原前列腺特異性膜抗原(PSMA)、前列腺酸性磷酸酶(PAP)、前列腺特異抗原(PSA)。美國FDA批準用于治療前列腺癌的Sipuleucel-T[9]。目前研究[10]比較深入的腫瘤抗原,已經(jīng)在腫瘤的診斷、預防和治療方面發(fā)揮著十分重要的作用。腫瘤特異抗原-Her-2/ neu-乳腺癌、前列腺癌、黑色素瘤抗原(MAGE)-黑色素瘤、卵巢癌、肝癌等[11-12]。

腫瘤相關抗原如腫瘤細胞裂解物致敏DC同樣能誘導CTL反應,而且還能誘導輔助性T細胞免疫反應。在兩個獨立品系的且腫瘤組織學不同小鼠,皮下注射腫瘤裂解物致敏DC,不僅減少腫瘤的體積,還有減少腫瘤肺轉(zhuǎn)移的作用[12]。相似的應用在小鼠肝癌細胞BNL1MEA.7R.1(BNL)、腎癌、同系GL261膠質(zhì)瘤、胰腺癌、惡性腦瘤及卵巢癌[13-15]。已大量研究[16-17]的與B淋巴瘤相關的CD20,與CA125糖蛋白相關的腫瘤有卵巢癌、子宮內(nèi)膜癌、宮頸癌、胰腺癌、腸癌、乳腺癌及肺癌。盡管腫瘤抗原研究取得了很大進展,但由于其獲得困難或特異性不強,采用全瘤組織細胞裂解物沖擊DC成為最直接的一種方法[18].最重要的是,腫瘤裂解物致敏-DC疫苗在人類惡性黑色素瘤、甲狀旁腺瘤、晚期乳腺和子宮癌、腎癌(RCC)及實體腫瘤中均有顯著的獲益[19-20]。

2 RNA轉(zhuǎn)染DC疫苗

與傳統(tǒng)疫苗相比,核酸疫苗可激發(fā)機體全面的免疫應答,其表達的抗原肽接近天然構(gòu)象,抗原性更強。而且,m RNA從小鼠腫瘤細胞株或從人類腫瘤冰凍切片中提取,可隨意擴增而不會喪失其相應的功能[21-22]。

腫瘤細胞的m RNA轉(zhuǎn)染DC能夠刺激荷瘤小鼠全能的CTL反應從而產(chǎn)生保護性免疫[23]。盡管大多有效的mRNA呈遞在人類血液細胞使用的電穿孔技術,大多數(shù)研究者均是用的m RNA/脂質(zhì)體復合物轉(zhuǎn)染的DCs[24]。因為,用腫瘤m RNA轉(zhuǎn)染DCs激活細胞內(nèi)信號機調(diào)節(jié)有效的抗原肽呈遞到MHC-1和MHC-II分子,故能顯著的誘導腫瘤特異性的效應T細胞的激活[25-26]。雖然這類疫苗在臨床的應用有限,但為癌癥患者誘導潛在的治療性多克隆T細胞反應提供了制備疫苗的策略[27-28]。

3 壞死或凋亡負荷的DC疫苗

DCs不僅能輕易的攝取可溶性腫瘤抗原如蛋白或免疫復合物,還能吞噬正在死亡的(如凋亡或壞死)腫瘤細胞,從而誘導保護性抗腫瘤免疫[29-31]。DCs識別和攝取凋亡細胞通過其特異性受體如Vb5, CD36或者磷脂酰絲氨酸受體[32],而攝取壞死細胞通過CD91和暴露在其細胞表面的(hot shock protein, HSP)受體[33-34]。近來一些比較性研究[35]表明,壞死和晚期凋亡細胞能同樣觸發(fā)DC成熟性改變從而誘導抗腫瘤免疫。DC吞噬壞死的腫瘤細胞依靠它們所表達的熱休克蛋白(HSP),進行成熟反應,伴隨化學炎癥因子和細胞因子、共刺激免疫分子表達上調(diào),從而在動物模型中誘導強烈的保護性抗腫瘤免疫[36-39]。

4 基因修飾的DC疫苗

將靶基因?qū)隓C制成的腫瘤疫苗是目前腫瘤疫苗研究的一大熱點,靶基因包括腫瘤相關抗原(TAA)和免疫調(diào)節(jié)蛋白如細胞因子或共刺激分子。將基因?qū)隓C的方法很多,包括陽離子脂質(zhì)、電穿孔法、基因槍、用陽離子CL22、非病毒載體T7構(gòu)建的質(zhì)粒DNA的復合物、病毒載體及病毒/聚陽離子復合物[40-42]。

4.1 腫瘤相關抗原轉(zhuǎn)染DC疫苗

在動物模型中,腫瘤相關抗原(TAA)導入DCs疫苗在體內(nèi)、外比腫瘤抗原致敏DC疫苗具有更強的抗腫瘤免疫反應,該疫苗能產(chǎn)生更強CD8+T淋巴細胞免疫反應,從而誘導出更強的抗腫瘤效應[43]。體外已經(jīng)證明,TAA導入DCs疫苗通過激活CD8+T淋巴細胞而提高抗腫瘤免疫反應[44]。MAGE-1, gp100,MART-1,h TRP2,p53,MUC-1及其他一些抗原基因已經(jīng)被用于轉(zhuǎn)入小鼠或人DCs從而誘導抗原特異性免疫反應[45-48]。

復制缺陷性重組腺病毒Ad Vs編碼的人gp100或MART-1黑色素瘤抗原已被用于轉(zhuǎn)入小鼠或人DCs。從轉(zhuǎn)移性黑色素瘤患者體內(nèi)獲取的gp100+制成的Ad2/gp100轉(zhuǎn)入DC獲得的疫苗在體外能誘導腫瘤特異性CTL反應[49]。相似的,HLA-A2+/ MART-1細胞株制成的Ad VMART1轉(zhuǎn)入DC疫苗能產(chǎn)生MART-1免疫肽特異性CTL反應,免疫荷黑色素瘤B16細胞的小鼠具有保護性免疫作用[50]。同樣,用重組腺病毒構(gòu)建的HER2/neu(Ad VNeu)轉(zhuǎn)入DC制成的疫苗,可抑制乳腺癌細胞過表達HER2/neu,同時具有保護性抗腫瘤免疫,能夠誘導針對乳腺癌細胞的CTL反應,體內(nèi)激活CD8+T和CD4+T淋巴細胞免疫反應。

4.2 免疫調(diào)節(jié)分子(細胞因子、趨化因子)轉(zhuǎn)染DC疫苗

上述提到的用抗原轉(zhuǎn)入DC制備的疫苗優(yōu)于直接用抗原或裂解物致敏DC,但需要尋找抗原性較強的抗原。用免疫調(diào)節(jié)蛋白構(gòu)建的DC疫苗可擴大DCs腫瘤抗原的能力,可用于任何類型的具有TAA的腫瘤。因為,DCs是天然專職的抗原呈遞細胞,能精確的呈遞細胞因子[51],所以,免疫調(diào)節(jié)分子(GMCSF,TNF-α、IL-12,次級淋巴組織趨化因子SLC,淋巴細胞趨化因子和CD40L等)修飾的DCs具有比相應的調(diào)節(jié)分子修飾腫瘤細胞疫苗更強的免疫調(diào)節(jié)能力。

GM-CS是DCs在體外生長和分化的必需因子。體內(nèi)免疫時,用GM-CSF轉(zhuǎn)染骨髓起源的BM-DCs的抗原呈遞能力相對模擬轉(zhuǎn)染或未處理的DC有很大的提高,同樣,在半抗原、蛋白抗原、或者腫瘤抗原誘導原始免疫反應方面也一樣。而這個能力的提高與該疫苗在體內(nèi)的增強遷移能力顯著相關。IL-12是一種異源二聚體細胞因子,由多種類型細胞產(chǎn)生包括DCs、巨噬細胞、白細胞和角質(zhì)形成細胞。DCs表達的IL-12轉(zhuǎn)基因疫苗與未轉(zhuǎn)染的DC相比能增強特異性抗腫瘤CTL反應。用該疫苗免疫荷瘤小鼠(MCA205、B16和D122),在第7天可見腫瘤開始消退,而接種的結(jié)腸腺癌則完全消退。

5 DC疫苗治療腫瘤的臨床研究進展

DCs在腫瘤免疫中的作用NK細胞的活化同樣受到DCs的調(diào)控,并反饋性調(diào)節(jié)DCs的功能[52]。除了產(chǎn)生有力的抗腫瘤免疫應答外,DCs也在腫瘤消除中發(fā)揮作用。Munich,S.等研究[36]報道DCs通過TNF超家族的配基殺死腫瘤,并可以直接抑制腫瘤細胞系的生長。在成熟過程中,DCs失去了它們有效攝取和加工抗原的能力,取而代之的是遷移能力的增加,使得它們能夠有效的遷移至引流淋巴結(jié)[53];另外,與iDCs相比,mDCs具有不同的細胞因子和生長因子表達譜[54-56]。

5.1 黑色素瘤

黑色素瘤是由異常黑素細胞過度增生引發(fā)的常見皮膚腫瘤,惡性程度極高,具有高發(fā)病率和高死亡率特點,研究[57]表明,免疫治療是黑素瘤的有效治療方法。一項對Ⅲ期惡性黑素瘤患者淋巴結(jié)清掃術后進行的DC疫苗臨床研究[58]證實,22例患者中,治療組的三年總生存率(OS)為68.0%,對照組僅為25.7%。對54個DC疫苗治療黑素瘤的臨床試驗進行回顧性分析,發(fā)現(xiàn)DC是否成熟、腫瘤Ⅲ期和Ⅳ期、是否使用佐劑、是否發(fā)生遲發(fā)性過敏反應及分泌IFN-γ的T細胞數(shù)量增加與否對疾病進展、臨床反應及疾病穩(wěn)定具有決定性影響。

5.2 前列腺癌

一項對于Sipuleucel-T成功上市至關重要的Ⅲ期臨床試驗共入組了512例前列腺癌患者(Sipuleucel-T組341例,安慰劑組171例),結(jié)果表明,與安慰劑組相比,Sipuleucel-T組的死亡風險下降了22%,中位生存期延長了4.1 mon(Sipuleucel-T組和安慰劑組分別為25.8和21.7 mon),3 a生存率提高了8.7%。兩組的客觀疾病進展時間無差異。Sipuleucel-T組多見的不良反應有寒顫、發(fā)燒和頭痛。一項Sipuleucel-T治療前列腺癌患者的Meta分析表明,納入分析的737例患者總生存期顯著增加。但是,疾病進展時間并沒有增加。受試者的恰當選擇從Sipuleucel-T臨床試驗的成功中得到充分體現(xiàn)。Dendreon公司選擇滿足如下入組標準的前列腺癌患者進行臨床研究:①無癥狀或輕微癥狀的轉(zhuǎn)移性去勢抵抗性前列腺癌患者;②預計生存期不小于6個月;③血清PSA水平不小于5 ng/m L;④血清睪酮水平不大于500 ng/L(17 nmol/L)(排除標準: (1)體能狀況評分不小于2(ECOG);(2)有內(nèi)臟轉(zhuǎn)移瘤;(3)病理長骨骨折;(4)脊髓壓迫)。⑤治療前28 d使用了糖皮質(zhì)激素、外放射治療、手術或全身治療(藥物或手術去勢除外);⑥在治療前28 d內(nèi)已經(jīng)開始或停止雙膦酸鹽治療;⑦之前已經(jīng)接受超過2個化療方案;⑧治療前3 mon內(nèi)已接受化療。

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[責任編輯 李麥產(chǎn)]

The Research Progress of Vaccine for Dendritic Cell tumor

WANG Ying1，LI Xichun2
（1.Eɑst-City Wɑrd of Sichun Province People's Hospitɑl，Chengdu，Sichun 610101，Chinɑ；2.Chengfei Hospitɑl of Aviɑtion industry Corporɑtion of Chinɑ，Chengdu，Sichuɑn 610092，Chinɑ）

Tumor immunotherapy has been treated as an in-creasingly effective treatment for the past ten years.In recent years，a lot of research has been carried out，which on the dendritic cell vaccine of tumor vaccine.It is reviewed that the progress of tumor dendritic cell vaccine in this paper.Our purpose is to try to clear the development of the tumor vaccine for the reader.

tumor；vaccine；dendritic cell

R73

A

1672―7606(2015)04―0279―06

2015-09-12

國家自然科學基金(81402402)

汪英(1981―),女,四川成都人,醫(yī)學博士,主治醫(yī)師,從事腫瘤分子靶向治療的基礎與臨床研究。