肿瘤树突状细胞疫苗研究进展

汪 英,李锡春

(1.四川省人民医院城东病区,四川成都610101;2.中航工业成飞医院,四川成都610092)

肿瘤树突状细胞疫苗研究进展

汪 英1,李锡春2

(1.四川省人民医院城东病区,四川成都610101;2.中航工业成飞医院,四川成都610092)

肿瘤免疫疗法在过去的十年被临床肿瘤学界视为一种越来越有效的治疗模式。近年来,对肿瘤疫苗中的树突状细胞疫苗进行了大量的研究。对肿瘤树突状细胞疫苗研究进展进行简述,目的是为读者梳理出肿瘤疫苗的发展脉络。

肿瘤;疫苗;树突状细胞

随着肿瘤生物学和免疫学的发展,肿瘤免疫治疗得到了迅速的发展。肿瘤免疫疗法在过去的十年被临床肿瘤学界视为一种越来越有效的治疗模式。FDA即批准了两个以免疫治疗为基础的产品,一个为治疗前列腺癌的Provenge(sipuleuce-T)疫苗,另一个为治疗黑色素瘤的抗细胞毒性T淋巴细胞相关抗原4(CTLA-4)的抗体ipilimumab疫苗。

肿瘤疫苗是指可以诱导机体产生针对肿瘤的特异性T细胞反应(包括CD8+和CD4+T细胞),以抑制或消除肿瘤生长、复发或转移的各种形式的疫苗。由于方法不同,可出现很多的肿瘤疫苗分类。目前比较公认的分类方法是依据肿瘤疫苗的来源、作用对象及构建载体来进行分类。通常肿瘤疫苗类型包括肿瘤细胞疫苗、基因工程疫苗、树突状细胞疫苗、病毒疫苗、多肽疫苗、核酸疫苗、抗独特性抗体疫苗等。1996年美国斯坦福大学医学中心Hsu等[1]在Nature Medicine上报道了全球首项树突状细胞(dendritic cell,DC)肿瘤疫苗临床研究,4例滤泡性B淋巴细胞肿瘤患者接受肿瘤抗原刺激的自体外周血来源DC细胞治疗,试验结果令人鼓舞。一项Meta分析表明,接受DC疫苗治疗的前列腺癌和肾细胞癌患者的目标应答率分别为7.7%和12.7%,临床受益率分别为54%和48%,总缓解率分别为10.6%和8.4%。现就肿瘤树突状细胞疫苗及其研究进展简述如下。

1973年,Steinman和Cohn发现具有树枝状突起的独特形态细胞,并将之命名为树突状细胞。DC参与多种疾病如感染、肿瘤、过敏及移植排斥的发生与发展。由于发现DC及其在获得性免疫应答中的作用,Steinman荣获2011年诺贝尔生理或医学奖并被誉为DC之父[2-3]。随着肿瘤免疫学的发展,DC作为肿瘤治疗手段受到了越来越多的关注并被寄予厚望。负载肿瘤抗原的DC疫苗被认为是最具潜能的一种肿瘤免疫治疗手段[4-5]。关于DC疫苗的研究主要有以下几方面。

1 肿瘤抗原肽致敏DC疫苗

肿瘤抗原肽致敏DC具有很好的靶向性,试验证明,在体内、外均能诱导MHC-1和MHC-2的特异性T细胞反应。在体外,单独的抗原肽则会引起特异性的CTL的耐受,而抗原肽致敏DC后能诱导针对肿瘤细胞的抗原特异性T细胞反应[4]。经DC呈递的人类或者小鼠的肿瘤抗原/肽能引起显著性的抗肿瘤免疫反应。特别是MHC限制性合成肿瘤相关肽,如黑色素瘤相关抗原,内源性逆转录病毒基因产品gp70/p15E,癌胚抗原(CEA),叶酸连接蛋白(FBP),前列腺特异性膜抗原(PMSA),survivin,MUC-1, HER2/neu和抗独特性衍生的蛋白质合成肽, bcr-ɑbl b3a2融合蛋白(ATGFKQSSKALQRPVAS)和一种合成的HPV16E7肽。肿瘤抗原肽致敏DC已在动物研究和临床试验中取得不同程度的效果[5-8]。与黑色素瘤相关的抗原gp100、MART-1、NA17及MAGE家族;与前列腺癌相关的抗原前列腺特异性膜抗原(PSMA)、前列腺酸性磷酸酶(PAP)、前列腺特异抗原(PSA)。美国FDA批准用于治疗前列腺癌的Sipuleucel-T[9]。目前研究[10]比较深入的肿瘤抗原,已经在肿瘤的诊断、预防和治疗方面发挥着十分重要的作用。肿瘤特异抗原-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]。

肿瘤相关抗原如肿瘤细胞裂解物致敏DC同样能诱导CTL反应,而且还能诱导辅助性T细胞免疫反应。在两个独立品系的且肿瘤组织学不同小鼠,皮下注射肿瘤裂解物致敏DC,不仅减少肿瘤的体积,还有减少肿瘤肺转移的作用[12]。相似的应用在小鼠肝癌细胞BNL1MEA.7R.1(BNL)、肾癌、同系GL261胶质瘤、胰腺癌、恶性脑瘤及卵巢癌[13-15]。已大量研究[16-17]的与B淋巴瘤相关的CD20,与CA125糖蛋白相关的肿瘤有卵巢癌、子宫内膜癌、宫颈癌、胰腺癌、肠癌、乳腺癌及肺癌。尽管肿瘤抗原研究取得了很大进展,但由于其获得困难或特异性不强,采用全瘤组织细胞裂解物冲击DC成为最直接的一种方法[18].最重要的是,肿瘤裂解物致敏-DC疫苗在人类恶性黑色素瘤、甲状旁腺瘤、晚期乳腺和子宫癌、肾癌(RCC)及实体肿瘤中均有显著的获益[19-20]。

2 RNA转染DC疫苗

与传统疫苗相比,核酸疫苗可激发机体全面的免疫应答,其表达的抗原肽接近天然构象,抗原性更强。而且,m RNA从小鼠肿瘤细胞株或从人类肿瘤冰冻切片中提取,可随意扩增而不会丧失其相应的功能[21-22]。

肿瘤细胞的m RNA转染DC能够刺激荷瘤小鼠全能的CTL反应从而产生保护性免疫[23]。尽管大多有效的mRNA呈递在人类血液细胞使用的电穿孔技术,大多数研究者均是用的m RNA/脂质体复合物转染的DCs[24]。因为,用肿瘤m RNA转染DCs激活细胞内信号机调节有效的抗原肽呈递到MHC-1和MHC-II分子,故能显著的诱导肿瘤特异性的效应T细胞的激活[25-26]。虽然这类疫苗在临床的应用有限,但为癌症患者诱导潜在的治疗性多克隆T细胞反应提供了制备疫苗的策略[27-28]。

3 坏死或凋亡负荷的DC疫苗

DCs不仅能轻易的摄取可溶性肿瘤抗原如蛋白或免疫复合物,还能吞噬正在死亡的(如凋亡或坏死)肿瘤细胞,从而诱导保护性抗肿瘤免疫[29-31]。DCs识别和摄取凋亡细胞通过其特异性受体如Vb5, CD36或者磷脂酰丝氨酸受体[32],而摄取坏死细胞通过CD91和暴露在其细胞表面的(hot shock protein, HSP)受体[33-34]。近来一些比较性研究[35]表明,坏死和晚期凋亡细胞能同样触发DC成熟性改变从而诱导抗肿瘤免疫。DC吞噬坏死的肿瘤细胞依靠它们所表达的热休克蛋白(HSP),进行成熟反应,伴随化学炎症因子和细胞因子、共刺激免疫分子表达上调,从而在动物模型中诱导强烈的保护性抗肿瘤免疫[36-39]。

4 基因修饰的DC疫苗

将靶基因导入DC制成的肿瘤疫苗是目前肿瘤疫苗研究的一大热点,靶基因包括肿瘤相关抗原(TAA)和免疫调节蛋白如细胞因子或共刺激分子。将基因导入DC的方法很多,包括阳离子脂质、电穿孔法、基因枪、用阳离子CL22、非病毒载体T7构建的质粒DNA的复合物、病毒载体及病毒/聚阳离子复合物[40-42]。

4.1 肿瘤相关抗原转染DC疫苗

在动物模型中,肿瘤相关抗原(TAA)导入DCs疫苗在体内、外比肿瘤抗原致敏DC疫苗具有更强的抗肿瘤免疫反应,该疫苗能产生更强CD8+T淋巴细胞免疫反应,从而诱导出更强的抗肿瘤效应[43]。体外已经证明,TAA导入DCs疫苗通过激活CD8+T淋巴细胞而提高抗肿瘤免疫反应[44]。MAGE-1, gp100,MART-1,h TRP2,p53,MUC-1及其他一些抗原基因已经被用于转入小鼠或人DCs从而诱导抗原特异性免疫反应[45-48]。

复制缺陷性重组腺病毒Ad Vs编码的人gp100或MART-1黑色素瘤抗原已被用于转入小鼠或人DCs。从转移性黑色素瘤患者体内获取的gp100+制成的Ad2/gp100转入DC获得的疫苗在体外能诱导肿瘤特异性CTL反应[49]。相似的,HLA-A2+/ MART-1细胞株制成的Ad VMART1转入DC疫苗能产生MART-1免疫肽特异性CTL反应,免疫荷黑色素瘤B16细胞的小鼠具有保护性免疫作用[50]。同样,用重组腺病毒构建的HER2/neu(Ad VNeu)转入DC制成的疫苗,可抑制乳腺癌细胞过表达HER2/neu,同时具有保护性抗肿瘤免疫,能够诱导针对乳腺癌细胞的CTL反应,体内激活CD8+T和CD4+T淋巴细胞免疫反应。

4.2 免疫调节分子(细胞因子、趋化因子)转染DC疫苗

上述提到的用抗原转入DC制备的疫苗优于直接用抗原或裂解物致敏DC,但需要寻找抗原性较强的抗原。用免疫调节蛋白构建的DC疫苗可扩大DCs肿瘤抗原的能力,可用于任何类型的具有TAA的肿瘤。因为,DCs是天然专职的抗原呈递细胞,能精确的呈递细胞因子[51],所以,免疫调节分子(GMCSF,TNF-α、IL-12,次级淋巴组织趋化因子SLC,淋巴细胞趋化因子和CD40L等)修饰的DCs具有比相应的调节分子修饰肿瘤细胞疫苗更强的免疫调节能力。

GM-CS是DCs在体外生长和分化的必需因子。体内免疫时,用GM-CSF转染骨髓起源的BM-DCs的抗原呈递能力相对模拟转染或未处理的DC有很大的提高,同样,在半抗原、蛋白抗原、或者肿瘤抗原诱导原始免疫反应方面也一样。而这个能力的提高与该疫苗在体内的增强迁移能力显著相关。IL-12是一种异源二聚体细胞因子,由多种类型细胞产生包括DCs、巨噬细胞、白细胞和角质形成细胞。DCs表达的IL-12转基因疫苗与未转染的DC相比能增强特异性抗肿瘤CTL反应。用该疫苗免疫荷瘤小鼠(MCA205、B16和D122),在第7天可见肿瘤开始消退,而接种的结肠腺癌则完全消退。

5 DC疫苗治疗肿瘤的临床研究进展

DCs在肿瘤免疫中的作用NK细胞的活化同样受到DCs的调控,并反馈性调节DCs的功能[52]。除了产生有力的抗肿瘤免疫应答外,DCs也在肿瘤消除中发挥作用。Munich,S.等研究[36]报道DCs通过TNF超家族的配基杀死肿瘤,并可以直接抑制肿瘤细胞系的生长。在成熟过程中,DCs失去了它们有效摄取和加工抗原的能力,取而代之的是迁移能力的增加,使得它们能够有效的迁移至引流淋巴结[53];另外,与iDCs相比,mDCs具有不同的细胞因子和生长因子表达谱[54-56]。

5.1 黑色素瘤

黑色素瘤是由异常黑素细胞过度增生引发的常见皮肤肿瘤,恶性程度极高,具有高发病率和高死亡率特点,研究[57]表明,免疫治疗是黑素瘤的有效治疗方法。一项对Ⅲ期恶性黑素瘤患者淋巴结清扫术后进行的DC疫苗临床研究[58]证实,22例患者中,治疗组的三年总生存率(OS)为68.0%,对照组仅为25.7%。对54个DC疫苗治疗黑素瘤的临床试验进行回顾性分析,发现DC是否成熟、肿瘤Ⅲ期和Ⅳ期、是否使用佐剂、是否发生迟发性过敏反应及分泌IFN-γ的T细胞数量增加与否对疾病进展、临床反应及疾病稳定具有决定性影响。

5.2 前列腺癌

一项对于Sipuleucel-T成功上市至关重要的Ⅲ期临床试验共入组了512例前列腺癌患者(Sipuleucel-T组341例,安慰剂组171例),结果表明,与安慰剂组相比,Sipuleucel-T组的死亡风险下降了22%,中位生存期延长了4.1 mon(Sipuleucel-T组和安慰剂组分别为25.8和21.7 mon),3 a生存率提高了8.7%。两组的客观疾病进展时间无差异。Sipuleucel-T组多见的不良反应有寒颤、发烧和头痛。一项Sipuleucel-T治疗前列腺癌患者的Meta分析表明,纳入分析的737例患者总生存期显著增加。但是,疾病进展时间并没有增加。受试者的恰当选择从Sipuleucel-T临床试验的成功中得到充分体现。Dendreon公司选择满足如下入组标准的前列腺癌患者进行临床研究:①无症状或轻微症状的转移性去势抵抗性前列腺癌患者;②预计生存期不小于6个月;③血清PSA水平不小于5 ng/m L;④血清睾酮水平不大于500 ng/L(17 nmol/L)(排除标准: (1)体能状况评分不小于2(ECOG);(2)有内脏转移瘤;(3)病理长骨骨折;(4)脊髓压迫)。⑤治疗前28 d使用了糖皮质激素、外放射治疗、手术或全身治疗(药物或手术去势除外);⑥在治疗前28 d内已经开始或停止双膦酸盐治疗;⑦之前已经接受超过2个化疗方案;⑧治疗前3 mon内已接受化疗。

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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

国家自然科学基金(81402402)

汪英(1981―),女,四川成都人,医学博士,主治医师,从事肿瘤分子靶向治疗的基础与临床研究。