景楚瑜(綜述) 張博恒(審校)

(復(fù)旦大學(xué)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(jìn)展

景楚瑜(綜述) 張博恒△(審校)

(復(fù)旦大學(xué)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(duì)免疫共抑制分子。以PD-1/PD-L1為靶點(diǎn)的藥物重新激活了機(jī)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(yù)測(cè)患者是否對(duì)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(yīng)率目前尚無定論。本文主要綜述了PD-1/PD-L1通路的作用機(jī)制、抗PD-1/PD-L1治療的研究進(jìn)展,并探討了預(yù)測(cè)抗PD-1/PD-L1療效的生物標(biāo)記物及聯(lián)合免疫治療的進(jìn)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(xué)改變的不斷累積。理論上,這些改變會(huì)使腫瘤細(xì)胞被人體免疫系統(tǒng)識(shí)別并清除,腫瘤中檢出的腫瘤浸潤性T淋巴細(xì)胞(tumor infiltrating lymphocytes,TILs)也反映了患者對(duì)自身腫瘤產(chǎn)生的免疫反應(yīng)[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(xì)胞處于一個(gè)高度免疫抑制的微環(huán)境中,可以通過肽-MHC復(fù)合物表達(dá)缺失[2]、分泌免疫抑制性細(xì)胞因子和介導(dǎo)負(fù)性共刺激信號(hào)等途徑逃避自身免疫反應(yīng)[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(jìn)展。免疫檢查點(diǎn)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(shù)、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(xì)胞毒性T淋巴細(xì)胞抗原-4(cytotoxic T-lymphocyte antigen-4,CTLA-4)治療,并且嚴(yán)重不良反應(yīng)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(huì)對(duì)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(yīng)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(chǔ)及臨床研究進(jìn)展,并探討了預(yù)測(cè)PD-1/PD-L1療效的潛在標(biāo)記物和聯(lián)合免疫治療的思路和進(jìn)展。

PD-1/PD-L通路的作用機(jī)制 PD-1(CD279)是可在T細(xì)胞、B細(xì)胞、單核細(xì)胞、自然殺傷細(xì)胞表面誘導(dǎo)表達(dá)的共抑制受體[5-7]。它由位于2號(hào)染色體長臂37區(qū)3帶(2q37.3)的PDCD1基因編碼,是一個(gè)55 kDa的跨膜蛋白[5]。PD-1在參與抗原識(shí)別的免疫細(xì)胞表面表達(dá)上調(diào),是免疫細(xì)胞活化的標(biāo)志之一[8]。在抗原清除后,這些細(xì)胞表面的PD-1表達(dá)則下調(diào)。在慢性病毒感染的背景下,PD-1的這一表達(dá)模式有助于平衡效應(yīng)T細(xì)胞的病原清除作用和對(duì)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(xì)胞中PD-L1和PD-L2的編碼基因均在9號(hào)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(diǎn):如PD-L1在造血細(xì)胞、非造血細(xì)胞及腫瘤細(xì)胞等多種細(xì)胞表面都廣泛表達(dá),而PD-L2只表達(dá)于抗原呈遞細(xì)胞和Th2細(xì)胞[12];PD-L1被認(rèn)為是PD-1的主要配體,但PD-L2對(duì)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(dǎo)表達(dá),而PD-L2則對(duì)IL-4更為敏感[14]。

T細(xì)胞活化主要依賴于CD3/CD28活化產(chǎn)生的共刺激信號(hào):與配體結(jié)合后,CD28配體依賴的酪氨酸磷酸化酶能促進(jìn)PI3K聚集并活化,使細(xì)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(jìn)細(xì)胞因子合成、糖轉(zhuǎn)運(yùn)蛋白表達(dá)、糖酵解和細(xì)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(xì)胞受體(T cell receptor,TCR)信號(hào)轉(zhuǎn)導(dǎo)[16-17]。PD-L1的另一個(gè)配體為B7-1(CD80),二者特異性結(jié)合可阻斷CD28:B7共刺激信號(hào),從而抑制T細(xì)胞活化[18]。此外,研究證實(shí)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(dǎo)調(diào)節(jié)性T細(xì)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(dǎo)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(jī)制主要有以下兩個(gè)假說:(1)固有機(jī)制:即腫瘤細(xì)胞本身的基因組或轉(zhuǎn)錄組變化導(dǎo)致PD-L1高表達(dá),最常見的是腫瘤固有的Akt、STAT3等信號(hào)通路的異常激活并誘導(dǎo)PD-L1高表達(dá),從而抑制細(xì)胞毒性T細(xì)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(huì)導(dǎo)致PIK3/Akt 信號(hào)通路的過度激活,而使下游的PD-L1表達(dá)增多[22];Green等[23]研究發(fā)現(xiàn),原發(fā)性縱膈大B細(xì)胞淋巴瘤和結(jié)節(jié)硬化型的霍奇金淋巴瘤中存在9號(hào)染色體短臂24區(qū)1帶拷貝數(shù)增加,這導(dǎo)致編碼基因位于9號(hào)染色體短臂的PD-L1和PD-L2高表達(dá)。除此之外,9p24擴(kuò)增可以激活JAK2/STAT,在促進(jìn)PD-1配體表達(dá)的同時(shí)促進(jìn)腫瘤生長。(2) 適應(yīng)性機(jī)制:即腫瘤細(xì)胞針對(duì)免疫微環(huán)境中免疫細(xì)胞對(duì)其清除作用的保護(hù)機(jī)制。腫瘤細(xì)胞在參與腫瘤清除的一系列細(xì)胞(即CD4+的Th1細(xì)胞、活化的T細(xì)胞、活化的自然殺傷細(xì)胞等)分泌的IFN-γ的誘導(dǎo)下高表達(dá)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(jìn)腫瘤的PD-L1表達(dá)。除了腫瘤細(xì)胞表面,TME中的TILs也可檢測(cè)出PD-L1的表達(dá)[25-27]。Herbst等[26]的研究顯示:TILs中PD-L1表達(dá)程度與腫瘤細(xì)胞的PD-L1表達(dá)程度相比,可以更好預(yù)測(cè)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(dá)PD-L1會(huì)加速甲基膽蒽誘導(dǎo)的鱗狀細(xì)胞癌模型的炎性致癌進(jìn)程,且誘導(dǎo)的腫瘤具有低表達(dá)E-鈣黏蛋白而高表達(dá)促進(jìn)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(duì)腫瘤發(fā)生和EMT的促進(jìn)作用[28]。近期,Kleffel等[29]在黑素瘤細(xì)胞表面檢測(cè)到PD-1表達(dá),并發(fā)現(xiàn)這些黑素瘤細(xì)胞可在沒有免疫細(xì)胞參與的情況下,進(jìn)行內(nèi)源性PD-1/PD-L1結(jié)合,通過激活mTOR通路信號(hào)通路來促進(jìn)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(yàn)的抗PD-1或者抗PD-L1的藥物[30]。這些治療的特點(diǎn)是患者耐受良好,大部分藥物在單藥I期臨床試驗(yàn)都沒有發(fā)現(xiàn)最大耐受劑量。目前已經(jīng)被美國FDA批準(zhǔn)上市的2個(gè)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(xì)胞介導(dǎo)的細(xì)胞毒性(antibody dependent cell-mediated cytotoxicity,ADCC) 和補(bǔ)體依賴的細(xì)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(dá)PD-1的TILs并使其抗腫瘤功能恢復(fù)的同時(shí),不對(duì)這些TILs產(chǎn)生ADCC和CDC介導(dǎo)的殺傷作用。

抗PD-L1抗體則主要應(yīng)用Fc段修飾的人源化IgG1,這類抗體因?yàn)镕c段的修飾不會(huì)產(chǎn)生ADCC作用,對(duì)表面表達(dá)PD-L1的TILs殺傷作用較弱;同時(shí),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(duì)T細(xì)胞活性的抑制作用,使腫瘤細(xì)胞能夠被T細(xì)胞識(shí)別并殺傷[31]。

抗PD-1藥物 第一個(gè)被美國FDA批準(zhǔn)用于臨床的抗PD-1治療藥物是Nivolumab。在臨床Ⅲ期試驗(yàn)中,Nivolumab和化療相比,在BRAF突變陰性或應(yīng)用Ipilimumab、BRAF抑制劑無效的進(jìn)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(zhǔn)用于Ipilimumab和BRAF抑制劑治療無效的進(jìn)展期黑色素瘤。

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

另外一種抗PD-1藥物是Pembrolizumab,在治療進(jìn)展期黑色素瘤的I期實(shí)驗(yàn)中,也被證實(shí)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(gè)包含495例患者的NSCLC臨床試驗(yàn)表明,Pembrolizumab的ORR為19.4%,在至少50%的腫瘤細(xì)胞表達(dá)PD-L1的患者亞組中,顯著高于腫瘤細(xì)胞PD-L1表達(dá)率不足50%的亞組[39]。隨后,Pembrolizumab被美國FDA認(rèn)定為突破性治療藥物,并批準(zhǔn)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(huì)阻止PD-L2和PD-1的相互作用。考慮到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(guān)不良反應(yīng)可能會(huì)更少。目前臨床試驗(yàn)中應(yīng)用的抗PD-L1藥物主要有BMS-936559、MEDI4736、MPDL3280A和MSB0010718C。最早用于臨床試驗(yàn)的BMS-936559對(duì)NSCLC、黑色素瘤、腎細(xì)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(yàn)公布的初期結(jié)果顯示,除了黑色素瘤、腎細(xì)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(yīng)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(yán)重的肺炎和腹瀉[42],這提示保留PD-L2通路活性可能會(huì)降低藥物毒性。在這些結(jié)果的推動(dòng)下,MPDL3280A被美國FDA認(rèn)定為晚期膀胱癌的突破性療法。

盡管抗PD-1/PD-L1治療對(duì)多種腫瘤都有治療效果,但其完整的抗腫瘤譜還需要進(jìn)一步研究證實(shí)。以下腫瘤可能對(duì)抗PD-1/PD-L1治療敏感,但是尚缺乏臨床試驗(yàn)數(shù)據(jù)支持:在肝細(xì)胞癌中,約25%的患者出現(xiàn)PD-L1的高表達(dá)[43],并且PD-L1的高表達(dá)患者較低表達(dá)或不表達(dá)PD-L1的患者預(yù)后更差,除此之外,PD-L1的表達(dá)水平還和FOXP3+的T淋巴細(xì)胞數(shù)目正相關(guān)[43],這些都提示了肝細(xì)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(jìn)行相關(guān)臨床試驗(yàn)有:(1) 驗(yàn)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(xì)胞癌和惡性膠質(zhì)瘤中療效的Ⅰb期/Ⅱ期臨床試驗(yàn)(NCT02423343);(2) 驗(yàn)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(xì)胞癌、NSCLC的療效的多中心Ⅰ期臨床試驗(yàn)(NCT02572687)。

肝內(nèi)膽管癌(intrahepatic cholangio-carcinoma,ICC)中有30%以上的PD-L1表達(dá)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(xué)研究也證實(shí),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(dá)免疫檢查點(diǎn)分子[47]。在以ICC患者為主的預(yù)后較差的亞組中,同時(shí)存在免疫檢查點(diǎn)的表達(dá)和較高的腫瘤突變負(fù)荷[47]。以上研究提示,ICC可能對(duì)抗免疫檢查點(diǎn)治療敏感,而其療效有待臨床試驗(yàn)證實(shí)。

預(yù)測(cè)抗PD-1/PD-L1療效的生物標(biāo)記物 抗PD-1/PD-L1治療雖然取得了良好的療效,但是因?yàn)槠滟M(fèi)用高昂,發(fā)現(xiàn)能準(zhǔn)確判斷治療敏感人群的生物標(biāo)記物顯得尤為重要。目前作為潛在預(yù)測(cè)抗PD-1/PD-L1療效的生物標(biāo)記物而被深入研究的主要有腫瘤的PD-L1表達(dá)水平、腫瘤特異性的突變相關(guān)抗原和腫瘤中存在的抗原特異性T細(xì)胞的數(shù)量[48]。

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

其他影響療效的指標(biāo) Herbst等[41]深入研究了接受MPDL3280A治療前后患者免疫指標(biāo)的變化,發(fā)現(xiàn)治療前標(biāo)本中TILs的PD-L1表達(dá)與療效關(guān)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(dá)和CX3CL1的低表達(dá)也與MPDL3280A的治療反應(yīng)相關(guān)[41]。Paul等[50]的研究則表明,治療前黑色素瘤標(biāo)本中腫瘤邊緣和內(nèi)部CD8+T細(xì)胞、PD-1陽性細(xì)胞和PD-L1陽性細(xì)胞的密度和抗PD-1治療的效果相關(guān),并且基于這幾個(gè)指標(biāo)的模型準(zhǔn)確預(yù)測(cè)了15名患者中13名患者對(duì)治療的反應(yīng)。近期研究發(fā)現(xiàn),高突變負(fù)荷的黑色素瘤細(xì)胞對(duì)抗CTLA-4治療的反應(yīng)更好[51]。與之類似,在NSCLC中,非同義突變導(dǎo)致了腫瘤突變負(fù)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(dá)水平與患者總生存期并無相關(guān)性,而ICC細(xì)胞表面HLA-I陽性并且PD-L1陰性或者低表達(dá)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(jìn)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(dá)缺失,這提示HLA-I的表達(dá)對(duì)免疫治療的療效也有一定的影響。

此外,PD-L1的檢測(cè)手段也值得關(guān)注。在ICC中,腫瘤PD-L1的表達(dá)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(cè)的異質(zhì)性并指出,目前的PD-L1檢測(cè)因?yàn)榭贵w親和力和特異性的不同,會(huì)有顯著的異質(zhì)性,這也使得PD-L1對(duì)于抗PD-1/PD-L1療效的預(yù)測(cè)價(jià)值需要在標(biāo)準(zhǔn)化檢測(cè)的基礎(chǔ)上再行深入探討。Mazel等[55]研究了乳腺癌循環(huán)腫瘤細(xì)胞PD-L1檢測(cè)的可行性,為PD-L1的檢測(cè)提供了新的思路。

上述可以用來預(yù)測(cè)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(xì)胞和腫瘤相互作用的復(fù)雜性,Teng等[56]根據(jù)TME中PD-L1表達(dá)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(dǎo)的PD-L1表達(dá);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(duì)抗PD-L1治療應(yīng)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(duì)治療并不敏感,且部分敏感患者在治療后并沒有達(dá)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(cè)序結(jié)果為患者制定多種免疫治療合用的方案,認(rèn)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(xì)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(dǎo)致免疫原性腫瘤細(xì)胞死亡;(3)使用免疫佐劑增強(qiáng)抗原呈遞細(xì)胞的功能;(4)利用激動(dòng)劑來提高效應(yīng)T細(xì)胞和巨噬細(xì)胞的功能[57]。根據(jù)患者特點(diǎn),合理聯(lián)合免疫檢查點(diǎn)阻滯劑、增強(qiáng)淋巴細(xì)胞功能的藥物、代謝靶向藥物、骨髓來源的細(xì)胞因子、趨化因子和免疫佐劑等藥物,理論上對(duì)各種類型TME的患者都會(huì)產(chǎn)生抗腫瘤效果。

聯(lián)合治療的相關(guān)臨床試驗(yàn)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(guān)不良反應(yīng)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(yàn)中,患者的疾病控制率高達(dá)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(dòng)物模型中被證實(shí)可以增強(qiáng)免疫治療的抗腫瘤作用[57],相關(guān)的聯(lián)合治療臨床試驗(yàn)也在相繼開展。

結(jié)語 從目前的臨床試驗(yàn)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(luò)十分復(fù)雜,這也提示盡管抗PD-1/PD-L1治療取得了突破性進(jìn)展,但是并不能夠完全掌控全局。目前抗PD-1/PD-L1治療領(lǐng)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(zhǔn)確可靠的療效預(yù)測(cè)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(chǔ)研究和臨床試驗(yàn)的共同推進(jìn),以抗PD-1/PD-L1治療為基礎(chǔ)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(xué)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).