尽管在过去几十年间,儿童恶性肿瘤所带来的死亡已经随着对疾病理解的深入以及诊断与治疗技术的飞速进展而显著减少,但仍有许多患儿不得不面对肿瘤复发、转移、耐药以及外科手术的无能为力[1]。近年来,针对肿瘤的靶向治疗不论是在成人还是在儿童肿瘤领域都有重要进展。然而,靶向治疗在临床前期体内、体外试验中观察到的疗效,亦或是在成人肿瘤治疗中的成功应用,并不代表其在儿童肿瘤的临床实践中也能取得同样的效果。本文综述靶向治疗在儿童实体肿瘤中的研究进展,为未来儿童实体肿瘤基础与临床研究的开展提供方向。
一、小分子阻滞剂的研究进展 (一) 细胞浆内的治疗靶点1. 丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路 在细胞增殖、生存和分化中发挥关键作用的MAPK信号通路在多种儿童肿瘤,如神经胶质瘤、恶性周围神经鞘瘤、黑色素瘤、朗格汉斯组织细胞增生症、横纹肌肉瘤(rhabdomyosarcoma, RMS)和神经母细胞瘤(neuroblastoma, NB)中,被发现存在变异或具有促癌功能[2]。司美替尼(selumetinib)是针对MAPK通路下游的效应分子MAPK激酶(MAPK kinase, MAPKK or MEK)1/2的选择性阻滞剂。2020年,Gross等[3]发表了司美替尼应用于Ⅰ型神经纤维瘤病(neurofibromatosis type 1,NF1)的临床二期试验成果:除了在70%的患儿中实现部分缓解(partial response, PR)外,还降低了患儿的疼痛指数,提升了健康相关生存质量,最终实现了约84%的3年无进展生存率(progression-free survival, PFS)。目前,司美替尼已被美国食品与药品管理局(Food and Drug Administration, FDA)批准应用于2岁以上儿童NF1的治疗。Eckstein等[4]则尝试将司美替尼的应用范围扩展到其他存在MAPK信号通路激活的复发/难治性儿童肿瘤(主要为高级别胶质瘤和RMS),但并未观察到客观缓解(objective response, OR)。另一种MEK阻滞剂卡比替尼(cobimetinib)则在56例6月龄至30岁实体肿瘤患者中实现了约5%的PR,且皆为低级别胶质细胞瘤(low grade glioblastoma, LGG),该比例在存在MAPK通路激活的LGG患者中约为8%[5]。
BRAF相关的基因变异,例如第600位密码子上的缬氨酸到谷氨酸氨基酸的替代(amino acid substitution for valine at position 600, V600E)或一种能导致KIAA1549和BRAF基因融合的串联重复在LGG中较为常见[6]。LGG患儿中存在BRAF V600E突变者约占19%,且对放疗、化疗反应不佳,长期生存情况也不如非BRAF V600E突变的LGG患儿[7]。B-Raf阻滞剂达拉菲尼(dabrafenib)在32例BRAF V600E突变阳性的LGG患儿中实现了约44%的OR率和约85%的1年PFS[8]。而MEK阻滞剂曲美替尼单药或与达拉菲尼联合应用于BRAF V600突变LGG实现了约25%的OR率,大于单药应用的15%的OR率,且不良反应更轻。目前,FDA已批准达拉菲尼与曲美替尼联合应用于成人以及6岁以上儿童BRAF突变肿瘤的治疗[9]。
2. 泛素化- 蛋白酶体系统 负责对细胞内蛋白进行降解的泛素化- 蛋白酶体系统也是肿瘤治疗的潜在靶标。神经前体细胞表达的发育下调蛋白8(neural precursor cell expressed developmentally down-regulated protein 8, NEDD8)是一种泛素样蛋白,其能够通过对cullin-RING连接酶(cullin-RING ligase, CRL)中的核心支架——cullin家族蛋白进行修饰来赋予其泛素连接酶的活性。MLN4924(pevonedistat)作为NEDD8活化酶(NEDD8 activating enzyme, NAE)的特异性抑制剂,能够阻止CRL的激活,进而干扰蛋白酶体系统的降解作用,使得其底物蛋白堆积,造成细胞死亡[10-11]。既往已有体外和体内研究证实MLN4924在儿童肿瘤中的抑癌作用[12]。目前,该药联合替莫唑胺和伊立替康在儿童复发/难治实体肿瘤的临床一期研究(ADVL1615)的阶段性成果已于2019年美国临床肿瘤学会(American Society of Clinical Oncology, ASCO)年会发表[13]。
(二) 细胞膜上的治疗靶点1. 间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK) ALK是一种可由点突变、拷贝数扩增或染色体异位等基因变异所激活的受体酪氨酸激酶,最初在间变大细胞淋巴瘤病例中被报道[14]。ALK抑制剂克唑替尼(crizotinib)在大多数存在ALK基因重排的儿童间变大细胞淋巴瘤及炎性肌纤维母细胞瘤中具有稳定且持续的治疗效果[15]。ALK突变在NB中也很常见,且复发NB往往具有更高的ALK突变频率[16-17]。目前,采用克唑替尼治疗ALK突变阳性、复发或难治NB的临床二期试验成果已于2021年发表,然而20例患者中仅有2例PR、1例完全缓解(complete response, CR)和2例病情稳定(stable disease, SD),且皆为ALK R1275Q突变[18]。这与临床前期研究的结果相符:由于F1174-ALK和F1245-ALK突变型与ATP亲和力更高,克唑替尼便难以与治疗靶点结合,因而相比R1275-ALK更容易耐药[19]。ALK突变在RMS也有报道,特别是存在PAX/FOXO1融合基因的腺泡型横纹肌肉瘤,其高表达与不良预后相关[20]。然而,包括克唑替尼在内的几种ALK阻滞剂在体内并未发挥出对RMS的抑制作用[21]。
2. 多激酶阻滞剂 许多抗癌新药不再局限于单个靶点,而是靶向多种受体酪氨酸激酶,其中卡博替尼(cabozantinib)在成人中已被批准用于治疗转移性甲状腺髓样癌和晚期肾癌[22-23]。Chuk等[24]于2018年发表了卡博替尼用于儿童复发/难治性实体肿瘤的一期临床试验结果,在41例4~18岁患儿中观察到4例PR:分别为2例甲状腺髓样癌,1例肾母细胞瘤和1例透明细胞肉瘤。在后续的二期临床试验中,Akshintala等纳入了骨肉瘤、尤文肉瘤、RMS、非RMS软组织肉瘤、肾母细胞瘤和罕见肿瘤共6个组别的2~30岁患者,其中10/29的骨肉瘤患者实现了4个月以上的病情控制(2例PR,8例SD),而其他肉瘤及肾母细胞瘤中未见OR,罕见肿瘤组中1/4的肾细胞癌和1/1的RET融合阳性的乳突状甲状腺癌实现了PR[25]。
另一种多激酶阻滞剂乐伐替尼(lenvatinib)与依托泊苷及异环磷酰胺的联合使用在骨肉瘤移植瘤中展现出了较强的抗肿瘤作用[26]。Gaspar等[27]于2022年发表了上述组合在2~25岁患者复发/难治性骨肉瘤中的临床试验结果:9%的患者实现了OR,71%的患者得到病情控制,获4个月PFS者占51%,高于既往研究中乐伐替尼单药或其他化疗药物应用于类似人群的PFS。
(三) 细胞核内的治疗靶点1. 组蛋白去乙酰化酶(histone deacetylase, HDAC) HDAC作为表观遗传调控的写入者,在肿瘤发生中也扮演着重要角色。HDAC(特别是Ⅰ类HDAC),在多种肿瘤中高表达,其对组蛋白的脱乙酰化作用使得组蛋白与DNA紧密相连,除抑制抑癌基因的表达之外,还可抑制细胞分化,而HDAC阻滞剂则有促进细胞增殖暂停、分化和凋亡的作用,其对包括未分化肉瘤、尤文肉瘤和NB的抑癌作用已在体内和体外得到证实[28-30]。Bukowinski等[31]于2021年报道了恩替诺特(entinostat),一种Ⅰ类HDAC的口服小分子阻滞剂在儿童肿瘤中的首次应用成果,结果显示该药的安全性良好,然而疗效不尽人意,仅1例室管膜瘤患儿实现SD。
2. Ser/Thr蛋白激酶家族 Wee1是一种Ser/Thr蛋白激酶家族的核激酶,可以通过抑制周期素依赖性激酶(cyclin dependent kinase, CDK1)来抑制存在DNA损伤的细胞由G2期进入有丝分裂期。对于p53失活的肿瘤细胞来说,Wee1反而起到了一种保护作用,可以阻止肿瘤细胞陷入复制叉崩溃(replication fork collapse)或有丝分裂崩溃(mitotic catastrophe)过程,进而避免细胞死亡。因此,抑制Wee1可以使得肿瘤细胞对DNA损伤类化疗药物更加敏感[32]。AZD1775(Adavosertib)是Wee1的一种高选择性小分子阻滞剂。Cole等[33]基于Wee1阻滞剂的作用机制,选择能够干扰DNA复制的伊立替康与AZD1775联合, 应用于儿童实体肿瘤:在该治疗方案的3个二期扩展队列[分别针对NB、弥漫性内生型桥脑胶质瘤(diffuse intrinsic pontine glioma, DIPG)和RMS]中,3/20的NB患者实现OR,其中2例存在ATRX基因缺陷,因此,该治疗方案除了对NB有一定疗效之外,其对ATRX突变肿瘤的效果也值得进一步研究[33-34]。此外,亦有学者尝试将AZD1775与放疗联合用于治疗DIPG,然而相较于既往对照并未观察到总体生存率(overall survival, OS)情况的改善[35]。
同属于Ser/Thr蛋白激酶家族的激光激酶A(Aurora A kinase, AAK)在有丝分裂中也起到了重要调控作用。AAK的小分子阻滞剂阿立赛替(alisertib/MLN8237)对多种儿童肿瘤的潜在疗效,包括NB、尤文肉瘤等,已得到了临床前期研究的支持[36]。值得一提的是,AAK在MYCN扩增的NB中有独特作用:AAK能够与E3连接酶F-box/WD重复蛋白7(F-box/WD repeat-containing protein 7, FBXW7)竞争,阻碍蛋白酶体对N-myc蛋白的降解[37]。阿立赛替与伊立替康联合应用在约21%的复发/难治性NB患者中实现了PR,1年PFS为34%;但与推测机制相悖的是,在MYCN未扩增的NB中反而疗效更佳[38]。而阿立赛替单药应用于复发/难治性实体肿瘤及白血病的二期研究则显示其疗效有限:117例2~21岁实体肿瘤患者中共5例OR,包括3例NB,1例肾母细胞瘤及1例肝母细胞瘤[39]。
3. 多腺苷二磷酸核糖聚合酶[poly(ADP-ribose) polymerase, PARP] PARP为一负责DNA单链损伤修复的蛋白家族,而PARP阻滞剂能通过与PARP-1/2的催化结构域结合并将其困在损伤的DNA处,引发复制叉损坏,进而诱导细胞凋亡[40-41]。涉及有核红细胞转化特异性(erythroblast transformation specific, ETS)家族转录因子的基因融合,例如EWS/FLI1或EWS/ERG,是尤文肉瘤中特征性基因变异,而这些融合蛋白与PARP存在相互作用,因此存在ETS家族基因融合的肿瘤对PARP阻滞剂格外敏感[42]。PARP阻滞剂他拉唑帕尼(talazoparib)与替莫唑胺联用在临床前期研究中被证实对尤文肉瘤、胶质瘤和肾母细胞瘤具有抗肿瘤作用。该组合应用于4~25岁患者的临床一/二期结果显示:10例尤文肉瘤中未观察到OR,仅有2例SD; 另有1/8的恶性胶质瘤实现了PR,但在3个疗程后因血小板减少而不得不停止治疗[43]。
二、单克隆抗体药物的研究进展单克隆抗体与肿瘤细胞表面的抗原分子结合后,巨噬细胞及自然杀伤(natural killer, NK)细胞能通过Fc受体识别肿瘤细胞,并通过吞噬作用或受体依赖的细胞毒作用(antibody-dependent cellular cytotoxicity,ADCC)将其清除。部分单克隆抗体,如针对免疫检查点抑制剂程序性死亡受体-1(programmed death-1, PD-1)的抗体和针对受体酪氨酸激酶的抗体,则单纯发挥阻断作用。
((一)) 受体酪氨酸激酶的单克隆抗体1. 血小板源性生长因子受体(platelet-derived growth factor receptor, PDGFR) 既往研究提示,PDGFR通路在多种儿童肿瘤(如胶质瘤、RMS、骨肉瘤和尤文肉瘤等)中发挥作用[44-45]。一些在儿童肿瘤中常见的基因变异,例如腺泡型横纹肌肉瘤(alveolar rhabdomyosarcoma, ARMS)标志性的PAX3/FOXO1基因融合,可能会导致该受体的异常高表达,且PDGFR在RMS中与不良预后有关[46-47]。Mascarenhaus等[48]于2021年报道了PDGFRα的单克隆抗体奥拉木单抗(olaratumab)治疗儿童实体肿瘤的一期临床试验结果,在68例接受奥拉木单抗联合化疗药物治疗的患者中,1例实现CR(RMS),3例实现PR(包括1例RMS和1例松果体母细胞瘤)。此外,我国还曾报道1例由VEGFR阻滞剂帕唑帕尼(pazopanib)联合奥拉木单抗治疗的肺转移胚胎型RMS并实现CR的成功案例[49]。尽管奥拉木单抗在后续成人随机双盲队列中被证实无法改善生存而被撤出市场,但其在儿童肿瘤(特别是软组织肉瘤)中的治疗潜能仍有一定的探索意义[50]。
2. 胰岛素样生长因子-1受体(insulin-like growth factor-1 receptor,IGF-1R) IGF-1R在RMS中高表达,且可能与其发生与进展相关[51]。然而IGF-1R的单克隆抗体西妥木单抗(cixutumumab)未在既往儿童实体肿瘤的研究中展现出令人满意的疗效[52-54]。Malempati等[55]尝试将西妥木单抗作为化疗的附加治疗,力图改善对转移性RMS的治疗效果,然而,该队列的3年无事件生存(event-free survival, EFS)率(约16%)甚至低于先前采用单纯化疗方案的队列(约38%)。有研究表明,RMS对IGF-1R抗体或阻滞药物的耐药性可能与YES/Src家族激酶(YES/Src family kinases, YES/SFK)信号通路的激活有关,因而同时抑制IGF-1R与YES/SFK也许可以达到治疗效果[56]。Akshintala等[57]选择联合应用另一种IGF-1R单抗盖尼塔单抗(ganitumab)与多激酶阻滞剂达沙替尼,并在临床一期试验纳入的9例儿童与年轻成人RMS中观察到1例PR,然而,其二期试验因为盖尼塔单抗的停产而提前终止[57]。
((二)) 肿瘤特异抗原的单克隆抗体GD2由于其在许多肿瘤细胞(儿童中主要为NB和肉瘤)表面高表达和正常组织低表达的特性,是肿瘤靶向治疗的理想靶点[58]。GD2的多种单克隆抗体已在NB中得到了深入的研究[59]。Ladenstein等[60]于2018年发表的多中心临床三期试验表明,在针对高危NB的GD2抗体地努妥昔单抗(dinutuximab)β巩固治疗中,白介素-2(interleukin-2, IL-2)未能延长1~20岁NB患者的EFS,且导致了更严重的毒性反应,因而不建议将IL-2作为地努妥昔单抗巩固治疗方案的一部分。Furman等[61]尝试将GD2单抗用于NB诱导治疗的临床二期试验研究,其中64例新诊断NB的患者接受了化疗与hu14.18K322A、粒细胞- 巨噬细胞集落刺激因子及IL-2的联合治疗,约97%的患者在诱导治疗的最后实现了PR或更好的疗效,3年EFS和OS分别为73.7%和86%,高于历史对照。GD2单抗在其他儿童肿瘤中也有相关研究报道:Hingorani等[62]于2022年发表了地努妥昔单抗与粒细胞- 巨噬细胞集落刺激因子(granulocyte-macrophage colony-stimulating factor, GM-CSF)联合应用于复发骨肉瘤治疗的二期临床试验结果:39例30岁以下患者中有11例实现12个月及以上的EFS,疾病控制率为28.2%,并未显著优于20%的历史基准。
((三)) 免疫检查点抑制剂针对PD-1/程序性死亡配体-1(programmed death ligand-1, PD-L1)或细胞毒性T细胞相关蛋白(cytotoxic T-lymphocyte-associated protein 4, CTLA-1)的单克隆抗体,即免疫检查点抑制剂的应用在成人肿瘤的治疗中已取得了振奋人心的结果。然而,儿童肿瘤的免疫特点与成人不同:儿童肿瘤较低的突变率和MHC-I的低表达量使得其免疫原性不足,浸润肿瘤的淋巴细胞相对较少。伊匹单抗(Ipilimumab)作为成人转移性黑色素瘤的治疗药物目前已获批上市[63]。然而,其单药应用于儿童实体肿瘤的结果并不理想,在一项纳入了33例21岁以下患者的一期临床试验中未观察到OR,其中12例黑色素瘤也仅有1例SD[64]。PD-1抗体纳武单抗(nivolumab)更适用于淋巴瘤:在Davis等[65]于2020年发表的临床一/二期试验中,3/10的霍奇金淋巴瘤和1/10的非霍奇金淋巴瘤患者实现了OR,然而在其他肿瘤类型中无一例实现OR。此后,Davis等[66]还探索了伊匹单抗与纳武单抗联合应用的可能,41例患者中有2例PR,分别为RMS和尤文肉瘤。
表达于肿瘤细胞表面的PD-L1同样也可作为靶点。PD-L1抗体阿替利珠单抗(atezolizumab)针对儿童和年轻成人实体肿瘤的临床一期和二期研究结果显示,仅5%的患者实现PR(其中有2例霍奇金淋巴瘤,1例非霍奇金淋巴瘤和1例恶性横纹样肿瘤)[67]。总体而言,免疫检查点抑制剂在儿童实体肿瘤中的治疗效果不如成人实体肿瘤理想,但在黑色素瘤、淋巴瘤和肉瘤的治疗中仍有继续探索的价值。
((四)) 抗体偶联药物(antibody drug conjugate, ADC)抗体还能够与药物、毒物或放射性同位素结合,形成抗体偶联药物(antibody drug conjugate, ADC),以将药物精准导向肿瘤。分化群(cluster of differentiation, CD)56在包括肾母细胞瘤、RMS、NB等在内的多种儿童肿瘤中都有表达[68]。洛沃妥珠单抗(lorvotuzumab)美登素(mertansine) (IMGN901)是将有丝分裂抑制剂与CD56单抗、洛沃妥珠单抗相交联的ADC,在临床前期试验中被证实对肾母细胞瘤、RMS和NB有效[69]。该药用于儿童及年轻成人上述肿瘤中的安全性尚可,但疗效有限,1/17的RMS患者实现PR,1/10的滑膜肉瘤实现CR[70]。此外,将靶向B7-同源物3(B7-Homolog3, B7H3)的单抗omburtamab在经过131I标记后局部注射的放射免疫疗法分别在累及腹膜的结缔组织增生性小圆细胞肿瘤和包括脑转移的NB在内的神经系统肿瘤中得到了尝试[71-72]。
三、过继细胞治疗的研究进展过继免疫细胞治疗需要从患者体内采集免疫细胞,在实验室中进行增殖和基因修饰等处理后,再将处理过的免疫细胞回输至患者体内。经过几十年的更新迭代,如今的嵌合抗原受体T细胞(chimeric antigen receptor T cell, CAR-T)技术赋予了过继T细胞较好的存续、扩增和靶向迁移能力,目前已在血液肿瘤中得到了成功应用,但针对实体肿瘤依旧存在许多挑战[73]。除T细胞之外,其他免疫细胞(如NK细胞)同样可以作为过继细胞治疗的工具。
在儿童实体肿瘤领域,GD2作为过继细胞治疗的靶点得到了较多的应用。Straathof等[74]于2020年发表的临床一期试验结果显示,采用CD28/CD3ζ信号转导片段的二代GD2-CAR-T细胞治疗NB未导致在靶/脱肿瘤(on-target/off tumor)效应所致的神经毒性,且接受大于≥108/m2 CAR-T细胞的6例患儿中,有3例观察到疗效。Heczey等[75]于2023年发表了抗GD2的CAR-自然杀伤T(natural killer T, NKT)细胞用于难治性NB中的前期成果:CAR-NKT细胞能够成功在体内增殖并定位到肿瘤转移位置,在12例患者中实现3例OR。GD2 CAR-T细胞在神经系统肿瘤中也得到了应用,Majzner等[76]于2021年发表的临床一期试验结果显示,CAR-T细胞能够成功定位到中枢神经系统,4例存在编码组蛋白H3的基因K27M突变(K27M mutation in genes encoding histone H3, H3K27M)的DIPG或弥漫性中线胶质瘤患者中,3例在影像学上及神经系统损害方面实现了好转。可见,GD2 CAR-T治疗在儿童实体肿瘤中有值得期待的应用前景。
四、儿童实体肿瘤靶向治疗的挑战儿童肿瘤与成人肿瘤不仅仅是疾病谱的区别,由于儿童肿瘤细胞中的基因突变较少,因此免疫原性更弱,缺乏肿瘤抗原。另一方面,对于靶向治疗而言,实体肿瘤相比血液系统肿瘤也更难以攻克。前者缺乏不在健康组织中表达的特异性抗原,因而容易导致靶/脱肿瘤效应。此外,不论是物理上的肿瘤基质和屏障,还是其周边免疫抑制性的肿瘤微环境,都阻碍着靶向药物或细胞精准针对肿瘤[77]。因此,能够帮助药物抵达和穿透实体肿瘤的特殊给药途径,以及针对肿瘤微环境中免疫抑制细胞(包括髓系来源抑制性细胞、肿瘤相关巨噬细胞和调节性T细胞)的免疫治疗,也许能够进一步提高靶向治疗的效率。
综上所述,靶向治疗在过去几年中,在儿童实体肿瘤领域取得了不少研究进展。从靶点丰富的小分子抑制剂,到单克隆抗体、ADC、免疫检查点抑制剂和CAR-T治疗等靶向治疗方法的百花齐放,靶向治疗为复发/难治性儿童实体肿瘤提供了许多新思路,但也面临着诸多挑战。
利益冲突 所有作者声明不存在利益冲突
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