抗PD-1/PD-L1治療在腫瘤治療中的研究進展

景楚瑜(綜述) 張博恒(審校)

(復旦大學附屬中山醫(yī)院肝腫瘤內(nèi)科 上海 200032)

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抗PD-1/PD-L1治療在腫瘤治療中的研究進展

景楚瑜(綜述) 張博恒△(審校)

(復旦大學附屬中山醫(yī)院肝腫瘤內(nèi)科 上海 200032)

程序性死亡蛋白-1(programmed death protein-1,PD-1)和程序性死亡配體-1(programmed death-ligand 1,PD-L1)是一對免疫共抑制分子。以PD-1/PD-L1為靶點的藥物重新激活了機體自身的抗腫瘤免疫并且在多種腫瘤中取得了良好而持久的療效。然而,如何預測患者是否對治療敏感及如何聯(lián)合其他治療提高抗PD-1/PD-L1治療的反應率目前尚無定論。本文主要綜述了PD-1/PD-L1通路的作用機制、抗PD-1/PD-L1治療的研究進展,并探討了預測抗PD-1/PD-L1療效的生物標記物及聯(lián)合免疫治療的進展。

腫瘤; 免疫治療; PD-1; PD-L1

腫瘤的發(fā)生源于基因和表觀遺傳學改變的不斷累積。理論上,這些改變會使腫瘤細胞被人體免疫系統(tǒng)識別并清除,腫瘤中檢出的腫瘤浸潤性T淋巴細胞(tumor infiltrating lymphocytes,TILs)也反映了患者對自身腫瘤產(chǎn)生的免疫反應[1]。然而,很少有腫瘤被自身的免疫系統(tǒng)消滅。越來越多的證據(jù)顯示,腫瘤細胞處于一個高度免疫抑制的微環(huán)境中,可以通過肽-MHC復合物表達缺失[2]、分泌免疫抑制性細胞因子和介導負性共刺激信號等途徑逃避自身免疫反應[3]。

腫瘤免疫治療的目的是通過拮抗腫瘤微環(huán)境(tumor microenvironment,TME)中的各種造成免疫抑制的因素,重新激活患者的腫瘤免疫。近年來,腫瘤的免疫治療取得了突破性的進展。免疫檢查點阻滯治療在許多腫瘤中都產(chǎn)生了顯著而持久的療效,這使得免疫治療有望成為手術、放療、化療之后的又一經(jīng)典的抗腫瘤治療。其中,抗程序性死亡蛋白-1(programmed death protein-1,PD-1)和程序性死亡配體-1(programmed death-ligand 1,PD-L1)治療的療效優(yōu)于抗細胞毒性T淋巴細胞抗原-4(cytotoxic T-lymphocyte antigen-4,CTLA-4)治療,并且嚴重不良反應的發(fā)生率更低[4],這也使得抗PD-1/PD-L1治療成為了最有前景的免疫治療方案。然而,如何判斷患者是否會對抗PD-1/PD-L1治療敏感,如何通過聯(lián)合其他治療提高抗PD-1/PD-L1治療的反應率還有待研究。本文主要綜述了抗PD-1/PD-L1治療的理論基礎及臨床研究進展,并探討了預測PD-1/PD-L1療效的潛在標記物和聯(lián)合免疫治療的思路和進展。

PD-1/PD-L通路的作用機制 PD-1(CD279)是可在T細胞、B細胞、單核細胞、自然殺傷細胞表面誘導表達的共抑制受體[5-7]。它由位于2號染色體長臂37區(qū)3帶(2q37.3)的PDCD1基因編碼,是一個55 kDa的跨膜蛋白[5]。PD-1在參與抗原識別的免疫細胞表面表達上調(diào),是免疫細胞活化的標志之一[8]。在抗原清除后,這些細胞表面的PD-1表達則下調(diào)。在慢性病毒感染的背景下,PD-1的這一表達模式有助于平衡效應T細胞的病原清除作用和對自身組織的損傷,從而降低了發(fā)生自身免疫病的概率[9]。

PD-1的兩大配體分別為PD-L1(B7-H1、CD274)[10]和 PD-L2(B7-DC、CD273)[11]。人類細胞中PD-L1和PD-L2的編碼基因均在9號染色體短臂24區(qū)2帶(9p24.2)[11]。雖然PD-L1和PD-L2的編碼基因和結(jié)構(gòu)相似,但是二者具有不同的特點:如PD-L1在造血細胞、非造血細胞及腫瘤細胞等多種細胞表面都廣泛表達,而PD-L2只表達于抗原呈遞細胞和Th2細胞[12];PD-L1被認為是PD-1的主要配體,但PD-L2對PD-1的親和力比PD-L1高出2～6倍[13];PD-L1主要在IFN-γ作用下誘導表達,而PD-L2則對IL-4更為敏感[14]。

T細胞活化主要依賴于CD3/CD28活化產(chǎn)生的共刺激信號:與配體結(jié)合后,CD28配體依賴的酪氨酸磷酸化酶能促進PI3K聚集并活化,使細胞內(nèi)3-磷酸化的脂質(zhì)增多。這些脂質(zhì)可以使Akt活化,促進細胞因子合成、糖轉(zhuǎn)運蛋白表達、糖酵解和細胞存活[15]。而在PD-1配體的參與下,PD-1和SHP-1、SHP-2包含的SH-2結(jié)構(gòu)域結(jié)合,通過使Akt激酶、 PI3K、ZAP-70、 PKC-θ和CD3δ等分子去磷酸化,抑制早期T細胞受體(T cell receptor,TCR)信號轉(zhuǎn)導[16-17]。PD-L1的另一個配體為B7-1(CD80),二者特異性結(jié)合可阻斷CD28:B7共刺激信號,從而抑制T細胞活化[18]。此外,研究證實PD-1/PD-L1通路激活后,極有可能通過下調(diào)Akt通路活性,誘導調(diào)節(jié)性T細胞的產(chǎn)生并維持其功能[19],從而起到免疫抑制的作用。

與PD-L1不同的是,PD-L2不能和B7-1結(jié)合[11],但能夠在無PD-1參與的情況下結(jié)合排斥導向分子b(repulsive guidance molecule b,RGMb),并參與維持呼吸系統(tǒng)的免疫耐受狀態(tài)[20]。

PD-1/PD-L1參與腫瘤免疫 PD-1/PD-L1參與腫瘤免疫逃逸的主要機制主要有以下兩個假說:(1)固有機制:即腫瘤細胞本身的基因組或轉(zhuǎn)錄組變化導致PD-L1高表達,最常見的是腫瘤固有的Akt、STAT3等信號通路的異常激活并誘導PD-L1高表達,從而抑制細胞毒性T細胞的活化[21-22];例如多種腫瘤中存在的PTEN基因的缺失,通常會導致PIK3/Akt 信號通路的過度激活,而使下游的PD-L1表達增多[22];Green等[23]研究發(fā)現(xiàn),原發(fā)性縱膈大B細胞淋巴瘤和結(jié)節(jié)硬化型的霍奇金淋巴瘤中存在9號染色體短臂24區(qū)1帶拷貝數(shù)增加,這導致編碼基因位于9號染色體短臂的PD-L1和PD-L2高表達。除此之外,9p24擴增可以激活JAK2/STAT,在促進PD-1配體表達的同時促進腫瘤生長。(2) 適應性機制:即腫瘤細胞針對免疫微環(huán)境中免疫細胞對其清除作用的保護機制。腫瘤細胞在參與腫瘤清除的一系列細胞(即CD4+的Th1細胞、活化的T細胞、活化的自然殺傷細胞等)分泌的IFN-γ的誘導下高表達PD-L1[24]。此外,IFN-γ還可以增加TME中有免疫抑制作用的吲哚胺2,3-加雙氧酶(indoleamine-2,3-dioxygenase,IDO)含量,促進腫瘤的PD-L1表達。除了腫瘤細胞表面,TME中的TILs也可檢測出PD-L1的表達[25-27]。Herbst等[26]的研究顯示:TILs中PD-L1表達程度與腫瘤細胞的PD-L1表達程度相比,可以更好預測抗PD-1治療的療效。

PD-1/PD-L1不僅參與腫瘤免疫的調(diào)節(jié),在腫瘤發(fā)生、生長、轉(zhuǎn)移過程中也發(fā)揮了一定作用。研究發(fā)現(xiàn),皮膚高表達PD-L1會加速甲基膽蒽誘導的鱗狀細胞癌模型的炎性致癌進程,且誘導的腫瘤具有低表達E-鈣黏蛋白而高表達促進上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition,EMT)的轉(zhuǎn)錄因子的特征,這提示了PD-L1對腫瘤發(fā)生和EMT的促進作用[28]。近期,Kleffel等[29]在黑素瘤細胞表面檢測到PD-1表達,并發(fā)現(xiàn)這些黑素瘤細胞可在沒有免疫細胞參與的情況下,進行內(nèi)源性PD-1/PD-L1結(jié)合,通過激活mTOR通路信號通路來促進自身增殖。

腫瘤的抗PD-1/PD-L1治療 目前為止,有許多用于臨床試驗的抗PD-1或者抗PD-L1的藥物[30]。這些治療的特點是患者耐受良好,大部分藥物在單藥I期臨床試驗都沒有發(fā)現(xiàn)最大耐受劑量。目前已經(jīng)被美國FDA批準上市的2個抗PD-1單抗為Nivolumab和Pembrolizumab,分別為全人源化IgG4和人源化IgG4。與IgG1和IgG3不同,IgG4抗體依賴的細胞介導的細胞毒性(antibody dependent cell-mediated cytotoxicity,ADCC) 和補體依賴的細胞毒作用 (complement-dependent cytotoxicity,CDC) 較弱[31]。這一特性保證了IgG4型的抗PD-1抗體,在靶向表達PD-1的TILs并使其抗腫瘤功能恢復的同時,不對這些TILs產(chǎn)生ADCC和CDC介導的殺傷作用。

抗PD-L1抗體則主要應用Fc段修飾的人源化IgG1,這類抗體因為Fc段的修飾不會產(chǎn)生ADCC作用,對表面表達PD-L1的TILs殺傷作用較弱;同時,它們可以阻止PD-L1和CD80結(jié)合,逆轉(zhuǎn)PD-L1和CD80結(jié)合后對T細胞活性的抑制作用,使腫瘤細胞能夠被T細胞識別并殺傷[31]。

抗PD-1藥物 第一個被美國FDA批準用于臨床的抗PD-1治療藥物是Nivolumab。在臨床Ⅲ期試驗中,Nivolumab和化療相比,在BRAF突變陰性或應用Ipilimumab、BRAF抑制劑無效的進展期黑色素瘤患者中都獲得了更高的客觀緩解率(objective response rate,ORR) (40%vs.13.9%和32%vs.11%)、持久的療效和更長的生存期[32-33]。這些結(jié)果使得Nivolumab在2014年被美國FDA批準用于Ipilimumab和BRAF抑制劑治療無效的進展期黑色素瘤。

值得一提的是,非小細胞肺癌(non-small cell lung cancer,NSCLC)并不被認為是高免疫原性腫瘤,并且被認為對免疫治療反應較差,但在Nivolumab的I期研究中,NSCLC的ORR為18%,其中鱗狀細胞NSCLC較非鱗狀細胞NSCLC對Nivolumab有著更高的反應率(33%vs.12%)[34-35]。最新的Ⅲ期隨機對照臨床試驗證實,在進展期鱗狀細胞NSCLC的患者中,Nivolumab比多西他賽單藥治療有更高的反應率(20%vs. 9%,P=0.008),降低了41%的死亡風險(P<0.001),并且毒性反應更輕[36]。這一試驗結(jié)果使Nivolumab被美國FDA批準用于接受含鉑類化療后病情進展的轉(zhuǎn)移性NSCLC。

另外一種抗PD-1藥物是Pembrolizumab,在治療進展期黑色素瘤的I期實驗中,也被證實安全有效,且在Ipilimumab敏感或抵抗的患者中的ORR無明顯區(qū)別[37-38]。一個包含495例患者的NSCLC臨床試驗表明,Pembrolizumab的ORR為19.4%,在至少50%的腫瘤細胞表達PD-L1的患者亞組中,顯著高于腫瘤細胞PD-L1表達率不足50%的亞組[39]。隨后,Pembrolizumab被美國FDA認定為突破性治療藥物,并批準用于Ipilimumab和BRAF抑制劑治療無效的難治性、轉(zhuǎn)移性黑色素瘤和NSCLC。

抗PD-L1藥物 抗PD-L1抗體能夠阻滯PD-L1/PD-1通路,但不會阻止PD-L2和PD-1的相互作用?？紤]到PD-L2/PD-1途徑在外周免疫穩(wěn)態(tài)中也發(fā)揮了作用[20],抗PD-L1抗體帶來的免疫相關不良反應可能會更少。目前臨床試驗中應用的抗PD-L1藥物主要有BMS-936559、MEDI4736、MPDL3280A和MSB0010718C。最早用于臨床試驗的BMS-936559對NSCLC、黑色素瘤、腎細胞癌、卵巢癌、胃癌、乳腺癌都產(chǎn)生了抗腫瘤作用[40]。MPDL3280A的I期臨床試驗公布的初期結(jié)果顯示,除了黑色素瘤、腎細胞癌等腫瘤,MPDL3280A在肉瘤、頭頸部腫瘤、結(jié)腸癌、胰腺癌、胃癌等腫瘤中也表現(xiàn)出了抗腫瘤活性[41]。在轉(zhuǎn)移性膀胱癌中,MPDL3280A的ORR為26%且反應持久[42]。安全性方面,和抗PD-1藥物不同的是,經(jīng)MPDL3280A治療的患者中未出現(xiàn)嚴重的肺炎和腹瀉[42],這提示保留PD-L2通路活性可能會降低藥物毒性。在這些結(jié)果的推動下,MPDL3280A被美國FDA認定為晚期膀胱癌的突破性療法。

盡管抗PD-1/PD-L1治療對多種腫瘤都有治療效果,但其完整的抗腫瘤譜還需要進一步研究證實。以下腫瘤可能對抗PD-1/PD-L1治療敏感,但是尚缺乏臨床試驗數(shù)據(jù)支持:在肝細胞癌中,約25%的患者出現(xiàn)PD-L1的高表達[43],并且PD-L1的高表達患者較低表達或不表達PD-L1的患者預后更差,除此之外,PD-L1的表達水平還和FOXP3+的T淋巴細胞數(shù)目正相關[43],這些都提示了肝細胞癌微環(huán)境中存在PD-1/PD-L1參與的免疫抑制。目前正在進行相關臨床試驗有:(1) 驗證抗PD-1單抗Nivolumab聯(lián)合TGF-β受體I激酶抑制劑Galunisertib在晚期NSCLC、肝細胞癌和惡性膠質(zhì)瘤中療效的Ⅰb期/Ⅱ期臨床試驗(NCT02423343);(2) 驗證人血管內(nèi)皮生長因子受體2拮抗劑Ramucirumab和抗PD-L1單抗MEDI4736聯(lián)合治療胃癌、胃食管交界處腺癌、肝細胞癌、NSCLC的療效的多中心Ⅰ期臨床試驗(NCT02572687)。

肝內(nèi)膽管癌(intrahepatic cholangio-carcinoma,ICC)中有30%以上的PD-L1表達率[2,44],這一結(jié)果與乳腺癌和卵巢癌相近[45-46]。最新的基因組學研究也證實,在包括ICC、膽囊癌在內(nèi)的膽道惡性腫瘤中,有45.8%的腫瘤表達免疫檢查點分子[47]。在以ICC患者為主的預后較差的亞組中,同時存在免疫檢查點的表達和較高的腫瘤突變負荷[47]。以上研究提示,ICC可能對抗免疫檢查點治療敏感,而其療效有待臨床試驗證實。

預測抗PD-1/PD-L1療效的生物標記物 抗PD-1/PD-L1治療雖然取得了良好的療效,但是因為其費用高昂,發(fā)現(xiàn)能準確判斷治療敏感人群的生物標記物顯得尤為重要。目前作為潛在預測抗PD-1/PD-L1療效的生物標記物而被深入研究的主要有腫瘤的PD-L1表達水平、腫瘤特異性的突變相關抗原和腫瘤中存在的抗原特異性T細胞的數(shù)量[48]。

腫瘤PD-L1表達與療效 最初,腫瘤PD-L1的表達水平被認為是預測療效最直觀的指標,然而后續(xù)研究證實腫瘤是否表達PD-L1對抗PD-1/PD-L1的療效預測效果并不理想。Nivolumab治療NSCLC的Ⅲ期臨床試驗(NCT01642004)證實了腫瘤的PD-L1表達既不能預測療效也不能預測抗PD-1治療之后的預后:許多患者的腫瘤細胞或TILs表面雖然無PD-L1表達,但也對Nivolumab敏感[36]。在Pembrolizumab治療轉(zhuǎn)移性NSCLC的臨床試驗中,PD-L1表達超過50%的亞組中ORR和療效顯著高于低表達或不表達PD-L1的亞組,然而在低表達或不表達PD-L1的亞組中,也有對Pembrolizumab有反應的患者[39]。Nivolumab治療晚期腎透明細胞癌臨床試驗同樣提示:腫瘤細胞表面高表達PD-L1 者預后更差,但不能用來預測抗PD-1治療的效果[49]。

其他影響療效的指標 Herbst等[41]深入研究了接受MPDL3280A治療前后患者免疫指標的變化,發(fā)現(xiàn)治療前標本中TILs的PD-L1表達與療效關系更加密切。除此之外,他們還發(fā)現(xiàn)治療前Th1基因、CTLA-4的表達和CX3CL1的低表達也與MPDL3280A的治療反應相關[41]。Paul等[50]的研究則表明,治療前黑色素瘤標本中腫瘤邊緣和內(nèi)部CD8+T細胞、PD-1陽性細胞和PD-L1陽性細胞的密度和抗PD-1治療的效果相關,并且基于這幾個指標的模型準確預測了15名患者中13名患者對治療的反應。近期研究發(fā)現(xiàn),高突變負荷的黑色素瘤細胞對抗CTLA-4治療的反應更好[51]。與之類似,在NSCLC中,非同義突變導致了腫瘤突變負荷的增加,從而提高了抗PD-1治療的敏感性[52]。Sabbatino等[2]發(fā)現(xiàn)在ICC腫瘤微環(huán)境中的PD-1/PD-L1表達水平與患者總生存期并無相關性,而ICC細胞表面HLA-I陽性并且PD-L1陰性或者低表達患者的總生存期顯著延長。Carretero等[53]則發(fā)現(xiàn)免疫治療后病情進展的黑色素瘤患者較病情好轉(zhuǎn)患者有明顯的HLA-I的表達缺失,這提示HLA-I的表達對免疫治療的療效也有一定的影響。

此外,PD-L1的檢測手段也值得關注。在ICC中,腫瘤PD-L1的表達水平出現(xiàn)了明顯的不一致性 (30%～100%)[2,44]。McLaughlin等[54]探討了NSCLC中PD-L1檢測的異質(zhì)性并指出,目前的PD-L1檢測因為抗體親和力和特異性的不同,會有顯著的異質(zhì)性,這也使得PD-L1對于抗PD-1/PD-L1療效的預測價值需要在標準化檢測的基礎上再行深入探討。Mazel等[55]研究了乳腺癌循環(huán)腫瘤細胞PD-L1檢測的可行性,為PD-L1的檢測提供了新的思路。

上述可以用來預測抗PD-1/PD-L1療效的多條線索,體現(xiàn)了腫瘤微環(huán)境中免疫細胞和腫瘤相互作用的復雜性,Teng等[56]根據(jù)TME中PD-L1表達和是否存在TILs,將TME分為4種類型:Ⅰ型:PD-L1陽性并有TILs,提示獲得性免疫耐受;Ⅱ型:PD-L1陰性無TILs,提示免疫忽略;Ⅲ型:PD-L1陽性無TILs,提示內(nèi)源性誘導的PD-L1表達;Ⅳ型:PD-L1陰性并有TILs,提示其他途徑的免疫抑制。理論上,Ⅰ型TME的患者對抗PD-L1治療應該最為敏感,而其他類型的患者則需要聯(lián)合治療來提高抗腫瘤效果。

聯(lián)合治療 盡管抗PD-1/PD-L1治療取得了良好的效果,但是大部分患者對治療并不敏感,且部分敏感患者在治療后并沒有達到完全緩解。Smyth等[57]建議結(jié)合Teng等[56]提出的TME分層和外顯子測序結(jié)果為患者制定多種免疫治療合用的方案,認為可以通過以下4種途徑來改變抑制性的TME:(1)通過減少免疫抑制性細胞及其分泌的抑制性介質(zhì)或阻滯抑制性受體來減少免疫抑制;(2)通過靶向治療導致免疫原性腫瘤細胞死亡;(3)使用免疫佐劑增強抗原呈遞細胞的功能;(4)利用激動劑來提高效應T細胞和巨噬細胞的功能[57]。根據(jù)患者特點,合理聯(lián)合免疫檢查點阻滯劑、增強淋巴細胞功能的藥物、代謝靶向藥物、骨髓來源的細胞因子、趨化因子和免疫佐劑等藥物,理論上對各種類型TME的患者都會產(chǎn)生抗腫瘤效果。

聯(lián)合治療的相關臨床試驗已經(jīng)獲得了初期成果:抗PD-1藥物Nivolumab和抗CTLA-4藥物Ipilimumab合用方案在轉(zhuǎn)移性黑色素瘤中獲得了更快速和明顯的療效,但是免疫相關不良反應也明顯增加[58]。在黑色素瘤中,抗CTLA-4單抗Ipilimumab和抗血管內(nèi)皮生長因子藥物Bevacizumab合用的Ⅰ期臨床試驗中,患者的疾病控制率高達67%[59]。此外,化療藥物、局部放療、疫苗和共刺激因子受體激活劑等在動物模型中被證實可以增強免疫治療的抗腫瘤作用[57],相關的聯(lián)合治療臨床試驗也在相繼開展。

結(jié)語 從目前的臨床試驗結(jié)果來看,抗PD-1/PD-L1治療的療效還有很大的發(fā)展空間。腫瘤微環(huán)境中的免疫調(diào)節(jié)網(wǎng)絡十分復雜,這也提示盡管抗PD-1/PD-L1治療取得了突破性進展,但是并不能夠完全掌控全局。目前抗PD-1/PD-L1治療領域亟待解決的問題是充分發(fā)掘?qū)筆D-1/PD-L1治療敏感的腫瘤、建立準確可靠的療效預測模型并與找到能和抗PD-1/PD-L1治療產(chǎn)生協(xié)同效果的治療手段。相信隨著基礎研究和臨床試驗的共同推進,以抗PD-1/PD-L1治療為基礎的免疫治療方案能夠成為腫瘤治療中又一里程碑。

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Research advancements of the anti-PD-1/PD-L1 therapy in oncotherapy

JING Chu-yu, ZHANG Bo-heng△

(DepartmentofHepaticOncology,ZhongshanHospital,FudanUniversity,Shanghai200032,China)

Programmed death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) are a pair of immune co-inhibitory molecules.Agents targeting the PD-1/PD-L1 pathway reactivated the autologous anti-tumor immune response and yielded strong and prolonged therapeutic effect in various cancer types.However,how to predict whether an individual is sensitive to the anti-PD-1/PD-L1 therapy and how to achieve higher response rates with combined therapies require further investigation.This review summarized the biological mechanism of the PD-1/PD-L1 pathway,the latest results of anti-PD-1/PD-L1 therapy,furthermore probed into potential biomarkers that predict the therapeutic effects and advancements in combined immune therapy.

tumor; immunotherapy; PD-1; PD-L1

國家自然科學基金(81173391)

R730

B

10.3969/j.issn.1672-8467.2016.06.013

2016-01-09;編輯:張秀峰)

△Corresponding author E-mail:zhang.boheng@zs-hospital.sh.cn

*This work was supported by the National Natural Science Foundation of China (81173391).