ACM  >> Vol. 8 No. 1 (February 2018)

作者:  

徐小萌:青岛大学医学院,山东 青岛;
韩真真,袁胜利:青岛市市立医院肿瘤科,山东 青岛

关键词:
免疫治疗联合治疗乳腺癌Immunotherapy Combination Therapy Breast Cancer

摘要:

近年来肿瘤免疫治疗(cancer immunotherapy, CIT)的发展使恶性肿瘤的治疗模式发生转变,尤其是黑色素瘤、肾癌、膀胱癌和肺癌,其显著提高了肿瘤的治疗敏感性,延长患者总生存时间(overall survival, OS)。乳腺癌通常被认为是一种“非炎症性”癌症,因此这种转变在治疗过程中没有那么明显。然而,一些乳腺癌的亚型,尤其是三阴性乳腺癌(Triple negative breast cancer, TNBC),多被认为是“炎症”,因此可能被证明是适合CIT的群体。本文回顾了肿瘤免疫周期理论和免疫抑制点的作用机制,就乳腺癌免疫治疗的研究进展及发现的问题进行综述。

Over the last few years, the developments around cancer immunotherapy (CIT) have led to a pa-radigm shift in the treatment of many different cancers, in particular melanoma, renal, bladder and lung cancers with a remarkable impact on response rate and, most importantly, overall survival. Breast cancer is most commonly considered to be a “non-inflamed” cancer and so this shift has been less marked within its treatment. However, some subsets of breast cancer, most notably triple negative breast cancer, are deemed to be more “inflamed” and therefore may prove to be an appropriate cohort for CIT. This review looks back at the theory of the cancer immunity cycle and mechanism of action behind immune checkpoint inhibitors and goes on to explore their roles in breast cancer, especially triple negative breast cancer.

1. 引言

CIT是指任何改变和/或增强肿瘤患者免疫系统功能以对抗肿瘤的治疗方法。最近对CIT的多项研究显示,既往的系统治疗对多种类型肿瘤疗效不显著,CIT使肿瘤的存活率有了前所未有的提高,如恶性黑色素瘤 [1] [2] 。且CIT耐受性良好,无毒性累积,也不具有传统肿瘤系统治疗(如化疗、放疗等)的一些副作用。这导致FDA批准了几项新的免疫疗法,例如CTLA-4单抗:Ipilimumab;PD-1抗体抑制剂:Pembrolizumab、Nivolumab;PD-L1抗体抑制剂:Atezolizumab、Durvalumab、Avelumab,并将免疫疗法整合到多种癌症的常规治疗中。

机体免疫系统检测和对抗癌细胞的能力主要基于两个关键因素。首先,免疫系统能够识别癌细胞与正常细胞的“不同”;癌细胞的“外来性”是免疫反应的一个关键因素,它与新抗原的表达有关,新抗原是一类蛋白质,通常在正常成人组织中难以发现。新抗原的产生与体细胞突变密切相关,因此,在不同的肿瘤类型中,更高的突变负荷与CIT方案的获益有关联也就不足为奇了。然而,越来越多的证据表明,不仅是体细胞突变的数量,而且是突变类型决定了对CIT的潜在反应。免疫应答的第二个决定因素是在需要时能够改变免疫细胞的数量和功能。该过程的一个重要参数是肿瘤淋巴细胞浸润的程度和模式。肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte, TILs)一方面与具有更高侵袭性的肿瘤类型有关,另一方面也与肿瘤对化疗的反应有关 [3] 。在TNBC中,TILs是一种独立的预后因素,而在ER阳性乳腺癌中并不具有预测性 [4] [5] 。也有证据表明,在Her2阳性乳腺癌和TNBC中,TILs可以增加治疗反应 [6] [7] 。

2. 免疫抑制点的作用机制和肿瘤免疫循环理论

淋巴细胞浸润的程度和模式和这些免疫细胞的活化状态,共同决定了宿主对肿瘤的反应。在这个复杂的系统中,免疫检查点在调节免疫反应中起着至关重要的作用。临床前和临床证据表明,肿瘤通过表达表面配体来逃避免疫系统的破坏,它可以抑制肿瘤特异性T细胞受体,并诱导免疫耐受 [8] [9] 。PD-1和PD-L1的相互作用在这个过程中起到核心作用。PD-1是免疫球蛋白超级家族中的一员,通过抑制T细胞活性来抑制免疫应答,同时PD-1也常在B细胞、髓细胞和自然杀伤细胞中表达 [10] [11] 。PD-1被它的配体PD-L1激活,在肿瘤细胞上表达活性。

免疫检查点的抑制作用是淋巴细胞抑制性受体(如PD-1和CTLA-4) [12] 抑制免疫系统来对抗自身免疫的过程。肿瘤细胞能够表达这些受体的配体(PD-L1和B7),从而抑制对它们的免疫反应。CTLA-4抗体(如Ipilimumab)能够阻断CTLA-4与B7之间的相互作用。PD-1 (Pembrolizumab和Nivolumab)和PD-L1 (Atezolizumab和Avelumab)的抗体能够抑制PD-1和PD-L1之间的通信 [13] 。通过解除对免疫系统的抑制,可以重新激活免疫系统,使T细胞再次识别和杀死癌细胞。

肿瘤免疫循环中描述了肿瘤宿主的相互作用 [14] 。这个循环的第一步是在肿瘤细胞死亡后释放癌细胞抗原。这一过程被称为免疫原性细胞死亡。抗原提呈细胞(APCs),如树突细胞,将这些抗原呈递到T细胞,导致淋巴组织启动和激活。细胞毒性T淋巴细胞(cytotoxic lymphocyte, CTL)进入血液,迁移到肿瘤微环境中,在那里它们能识别、结合并最终杀死癌细胞 [14] 。免疫疗法的最终目的是使这一循环永久化,从而导致大量的肿瘤细胞死亡。

3. “炎症性”肿瘤——乳腺癌

不同肿瘤类型的预存免疫性和它们诱发免疫反应的能力之间存在显著差异。高预存免疫性的恶性肿瘤已经被描述为“炎症性”肿瘤,这种类型肿瘤的特点是可见TILs,肿瘤或免疫细胞中PD-L1表达阳性,CD8+T细胞高密度表达,存在大量分泌γ干扰素(IFNγ)的细胞毒性T细胞 [15] 。有越来越多的临床证据表明,针对于PD-1/PD-L1的单剂免疫检查点抑制剂在这些“炎症性”肿瘤中最有效 [16] [17] 。非炎症性肿瘤一般不容易被TILs浸润,呈现PD-L1的低表达,其特点是抗原呈递少见 [18] 。

与其他疾病相比,可被视为“炎症性”肿瘤的乳腺癌比例相对较小,而且在不同亚型之间存在很大差异。TNBC或HER-2阳性乳腺癌通常比激素敏感型乳腺癌的免疫原性高,它们有更高比例的TILs [19] 。即使在激素敏感型乳腺癌中也存在免疫原性的差异,与典型的Luminal A型乳腺癌相比,Luminal B型乳腺癌免疫原性更强。

TNBC通常被认为是最像“炎症”的乳腺癌亚型,尽管TNBC不同亚型之间存在显著差异。区别于不同的免疫活性,Burstein等 [20] 通过基因组分析将TNBC分为4个亚型,包括腔型/雄激素受体型(luminal/androgen receptor, LAR)、间质型(mesenchymal, MES)、基底样/免疫抑制性(basal-like/immune-suppressed, BLIS)和基底样/免疫激活型(basal-like/immune activated, BLIA)。迄今,这种异质性尚未在临床试验中得到充分考虑,这是新的治疗策略发展面临挑战的原因之一。临床前的研究表明,抗PD-1抗体可以提高抗HER2靶向治疗的治疗活性 [21] ,以致于出现大量检查点抑制剂与抗Her-2抗体结合的试验设计,然而,这些研究目前还没有报告具体数据。免疫检查点抑制剂在ER阳性乳腺癌中的作用尚不清楚。ER阳性乳腺癌,特别是Luminal A型,通常表现出“非炎症”性,不太可能从单药CIT中获益。免疫治疗药物在这一亚群中的有效性需要联合化疗或靶向治疗,通过诱导免疫反应来激活肿瘤的微环境,在检查点抑制剂可能获益前激活肿瘤免疫循环。

4. 单药肿瘤免疫治疗

多数乳腺癌早期的CIT试验都集中在TNBC上,并且已经报道了针对PD-1或PD-L1的单药免疫检查点抑制剂的数据。

在KEYNOTE-012第一阶段研究的扩展阶段 [22] ,对32例转移性TNBC的抗PD-1抑制剂Pembrolizumab的疗效进行了探讨。所有入组患者肿瘤均为PD-L1阳性,通过免疫组化法定义为,肿瘤或免疫细胞1%的基质中见PD-L1表达。大多数患者(27例)入组前接受过转移性乳腺癌的系统治疗,中位接受治疗数量为2种,最多达9种,所有患者既往均接受过辅助或新辅助治疗。23例(71.9%)、32例(100%)和19例(59.4%)患者曾接受过蒽环类、紫杉类和铂类为基础的药物化疗。给予患者Pembrolizumab 10 mg/kg,每两周一次,共24个月或直到病情进展,或不能耐受毒性。临床稳定的患者,若存在影像学进展证据,可以继续用药直到疾病进展得到确认。在27例可评估抗肿瘤活性的患者中,总体反应率为18.5%,中位反应时间为17.9周。此外,25.9%患者评价疗效显示稳定,临床受益率(clinical benefit rate, CBR)为44.4%。

目前,在TNBC中临床数据较多的是PD-L1抑制剂Atezolizumab,在2017年美国癌症研究协会(American Association for Cancer Research)年会上,Schmid等 [23] 公布了一项Atezolizumab单药治疗转移性TNBC的I期临床试验结果。本试验共纳入115例患者,最初只选取免疫细胞5% PD-L1表达的患者,但随后也纳入了PD-L1低表达或表达缺失的患者。入组患者中,17%既往接受过一线治疗,24%的患者在转移前接受过1次治疗,58%接受2次治疗。98例(85%)、108例(94%)和67例(58%)患者分别接受过蒽环类、紫杉类和铂类为基础的化疗。根据RECIST标准评价,Atzolizumab治疗后患者的客观缓解率(Objective Response Rate, ORR)为10%,根据改良的RECIST标准评价,患者ORR为13%。此外,接受Atzolizumab一线CIT治疗的患者,ORR为26%,接受二线治疗的患者,ORR为4%,而接受三线及以上治疗的患者,ORR为8%。根据上述研究结果,我们认为,患者越是早期治疗,对CIT的反应越高。而这项研究也是目前乳腺癌免疫治疗随访时间最长的一项研究,接受Atzolizumab一线治疗的患者,1年及2年整体生存率分别为63%及47%,而接受2线及2线以上治疗的患者,1年及2年的整体生存率则分别为37%及18%。

此外,Pembrolizumab单药治疗转移性TNBC对比单药化疗的研究目前正在进行,将进一步明确单药CIT的作用。

5. 联合肿瘤免疫治疗

虽然大量免疫检查点抑制剂的研究已经证实了单药CIA的作用,但只有相对较少的患者能从中获益,因此,未来研究的方向应集中于联合治疗策略,以增加可能受益于CIT的患者比例。临床前研究表明,协同作用的部分原因是化疗能降低抑制肿瘤免疫反应的调节性T细胞的活性 [24] 。此外,有研究表明,化疗可以初步“启动”患者的免疫系统 [14] [25] 。如前所述,肿瘤免疫循环的第一步是通过癌细胞死亡释放癌细胞抗原 [14] 。化疗药物引起癌细胞死亡,因此抗原释放,使APCs向T细胞呈现这些抗原,从而启动循环。免疫治疗药物阻止了免疫系统的停止,使T细胞能够继续消灭癌细胞,这反过来又进一步延续免疫循环。这可以被认为是将癌细胞转化为内源性肿瘤疫苗 [26] 。

纽约大学的Sylvia Adams等 [27] 对PD-L1抑制剂Atezolizumab联合白蛋白紫杉醇治疗转移性TNBC的安全性及疗效进行研究。试验安全性队列共纳入了32例患者,中位年龄为55.5岁,中位随访时间5.2月(范围0.6~12.6月)。入组患者注射Atezolizumab 800 mg,每两周一次(第1和第15天),白蛋白紫杉醇125 mg/m2,每周一次(第1、8和第15天),4周为一个周期,用药至病情进展。结果显示无治疗相关死亡事件,56%患者观察到3~4级副作用,主要为白细胞减少(41%)、血小板减少(9%)以及贫血(6%)。疗效队列纳入24例患者,随访时间均大于3个月,9例接受Atezolizumab联合白蛋白紫杉醇一线治疗,8例接受二线治疗,7例接受三线或以上治疗。结果显示接受一线治疗的患者相比二线或以上治疗的患者可获得更高的有效率。一线治疗时,11.1%患者获得完全缓解(complete response, CR),77.8%患者获得部分缓解(partial response, PR),11.1%患者获得稳定(stable disease, SD),没有患者出现疾病进展(progressive disease, PD),ORR为88.9%。

6. 免疫治疗的展望

虽然肿瘤免疫治疗前景光明,但它仍处在起步阶段,免疫治疗的最佳时机和最佳联合方式还有待更多研究来证实。对于晚期乳腺癌患者,免疫检查点抑制剂在一些小样本的研究中显示出一定疗效,但仍需要进行大样本的临床研究,进一步为我们的临床治疗提供指导。目前关于乳腺癌免疫治疗的临床实验多集中于晚期或转移性乳腺癌,至于早期乳腺癌能否从CIT中获益,仍需要大量实验数据支持。另外,如何提高“非炎症性”肿瘤,如ER阳性、Her2阴性乳腺癌患者的反应率,从而提高远期生存,彻底改变当前乳腺癌治疗局面,这对我们来说是挑战,也是未来可考虑的研究方向。

文章引用:
徐小萌, 韩真真, 袁胜利. 乳腺癌免疫治疗新进展[J]. 临床医学进展, 2018, 8(1): 47-52. https://doi.org/10.12677/ACM.2018.81009

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