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    復(fù)發(fā)/難治彌漫性大B細(xì)胞淋巴瘤治療進(jìn)展

    2017-12-18 06:10:43高廣勛
    臨床薈萃 2017年12期
    關(guān)鍵詞:亞型淋巴瘤抑制劑

    張 娜, 高廣勛

    (空軍軍醫(yī)大學(xué) 第四軍醫(yī)大學(xué)西京醫(yī)院 血液內(nèi)科,陜西 西安 710032)

    ·專(zhuān)題·

    復(fù)發(fā)/難治彌漫性大B細(xì)胞淋巴瘤治療進(jìn)展

    張 娜, 高廣勛

    (空軍軍醫(yī)大學(xué) 第四軍醫(yī)大學(xué)西京醫(yī)院 血液內(nèi)科,陜西 西安 710032)

    彌漫性大B細(xì)胞淋巴瘤(DLBCL)是一類(lèi)異質(zhì)性明顯的淋巴系統(tǒng)惡性腫瘤,也是最常見(jiàn)的非霍奇金淋巴瘤(NHL)亞型,發(fā)病率日益增高,極大危害人類(lèi)健康。經(jīng)過(guò)標(biāo)準(zhǔn)利妥昔單抗聯(lián)合環(huán)磷酰胺、阿霉素、長(zhǎng)春新堿和潑尼松(R-CHOP)方案治療,超過(guò)60%患者的生存期顯著提高,然而仍有約30%患者出現(xiàn)疾病復(fù)發(fā)或難治,預(yù)后很差。通過(guò)對(duì)基因表達(dá)譜、耐藥分子機(jī)制等深入研究,新化療方案及新藥不斷探索,嵌合抗原受體T細(xì)胞治療等新手段引入,為個(gè)體化精準(zhǔn)治療復(fù)發(fā)/難治DLBCL帶來(lái)了希望。本文采用文獻(xiàn)回顧的方式,重點(diǎn)探討新藥及嵌合抗原受體T細(xì)胞(CART)治療技術(shù)在復(fù)發(fā)/難治DLBCL中的治療進(jìn)展。

    淋巴瘤, B細(xì)胞;復(fù)發(fā);受體,抗原,T細(xì)胞; 治療

    高廣勛,空軍軍醫(yī)大學(xué)(第四軍醫(yī)大學(xué))西京醫(yī)院血液內(nèi)科主任。醫(yī)學(xué)博士,副主任醫(yī)師,副教授,碩士研究生導(dǎo)師,美國(guó)紐約大學(xué)醫(yī)學(xué)院訪問(wèn)學(xué)者?,F(xiàn)任中華醫(yī)學(xué)會(huì)血液學(xué)分會(huì)青年委員會(huì)委員,中國(guó)老年協(xié)會(huì)血液學(xué)委員會(huì)常委兼副總干事,中國(guó)抗癌協(xié)會(huì)血液腫瘤委員會(huì)青年委員會(huì)委員,全軍血液學(xué)會(huì)青年委員會(huì)副主任委員,西安市醫(yī)學(xué)會(huì)血液學(xué)會(huì)副主任委員,陜西省血液學(xué)會(huì)青年委員會(huì)副主任委員,中國(guó)醫(yī)師協(xié)會(huì)整合血液學(xué)分會(huì)委員兼秘書(shū),陜西省抗癌協(xié)會(huì)白血病專(zhuān)業(yè)委員會(huì)常委,陜西省抗癌協(xié)會(huì)淋巴瘤專(zhuān)業(yè)委員會(huì)常委兼秘書(shū)。負(fù)責(zé)國(guó)科金、陜西省自然科學(xué)基金、吳階平醫(yī)學(xué)基金多項(xiàng),第四軍醫(yī)大學(xué)教學(xué)課題、新技術(shù)新業(yè)務(wù)項(xiàng)目多項(xiàng),主編(副主編)專(zhuān)著4部,第一或通訊作者發(fā)表論文30余篇,其中SCI收錄15篇。

    非霍奇金淋巴瘤(NHL)是一類(lèi)異質(zhì)性明顯的惡性血液病,按照組織病理類(lèi)型分為B細(xì)胞NHL(B-NHL)和T/NK細(xì)胞NHL(T/NK-NHL)。在B-NHL中,最常見(jiàn)的亞型為彌漫性大B細(xì)胞淋巴瘤(DLBCL)。2016版世界衛(wèi)生組織(WHO)根據(jù)形態(tài)學(xué)、生物學(xué)行為、臨床表現(xiàn)等將DLBCL分為非特指型(NOS)、亞型和其他獨(dú)立型3大類(lèi)。其中DLBCL-NOS最為常見(jiàn),根據(jù)細(xì)胞起源和基因表達(dá)譜DLBCL-NOS又被分為:生發(fā)中心B細(xì)胞型(GCB)、活化B細(xì)胞型(ABC)和第3型,現(xiàn)將ABC型和第3型統(tǒng)稱(chēng)為Non-GCB型[1-5]。

    利妥昔單抗(R)時(shí)代前,標(biāo)準(zhǔn)一線治療方案能使大約50%~60% DLBCL患者達(dá)到并維持完全緩解(CR);抗CD20單克隆抗體-R聯(lián)合環(huán)磷酰胺、阿霉素、長(zhǎng)春新堿和潑尼松(CHOP)應(yīng)用于臨床顯著提高治療反應(yīng)(CR率升至75%左右)[6-8]。然而,仍有部分患者出現(xiàn)治療無(wú)應(yīng)答[尚未達(dá)到部分緩解(PR)]或疾病復(fù)發(fā),被認(rèn)為是復(fù)發(fā)/難治性DLBCL(rr DLBCL)。rr DLBCL患者預(yù)后差[9-11],其中只有23%~29%對(duì)二線治療有應(yīng)答[12-13],中位總生存期(OS)僅為4個(gè)月,中位無(wú)進(jìn)展生存期(PFS)僅為3個(gè)月,而對(duì)三線化療的反應(yīng)率僅為14%[12, 14]。初次自體造血干細(xì)胞移植(ASCT)后復(fù)發(fā)患者的中位OS為10個(gè)月[10, 15]。如何有效控制疾病進(jìn)展,延長(zhǎng)生存仍是一項(xiàng)亟待解決的臨床難題。通過(guò)對(duì)耐藥分子機(jī)制研究,挽救性化療方案優(yōu)化,新藥物探索,新治療方法引入為攻克rr DLBCL帶來(lái)新希望。

    1 標(biāo)準(zhǔn)治療

    PARMA[9]研究發(fā)現(xiàn)高劑量化療(HDC)聯(lián)合ASCT可以顯著改善rr DLBCL患者預(yù)后,因此,HDC-ASCT被建議作為rr DLBCL的標(biāo)準(zhǔn)治療。此外,荷蘭比利時(shí)血液腫瘤協(xié)作組進(jìn)行的一項(xiàng)前瞻性隨機(jī)對(duì)照研究(Hovon-44)證實(shí)R聯(lián)合HDC-ASCT能使患者明確獲益[16]。目前R-HDC-ASCT已成為對(duì)化療依舊敏感的rr-DLBCL的主要治療方法[17]。另一方面,R維持治療對(duì)于ASCT后復(fù)發(fā)的DLBCL似乎沒(méi)有明確意義[18]。

    治療rr DLBCL常采用的化療方案包括利妥昔單抗聯(lián)合依托泊苷、類(lèi)固醇、阿糖胞苷、順鉑(R-ESHAP);利妥昔單抗聯(lián)合卡鉑、異環(huán)磷酰胺、依托泊苷(R-ICE);依托泊苷、阿霉素、環(huán)磷酰胺、長(zhǎng)春新堿、強(qiáng)的松和利妥昔單抗(DA-EPOCH-R);利妥昔單抗聯(lián)合吉西他濱、奧沙利鉑(R-GEMOX);利妥昔單抗聯(lián)合吉西他濱、順鉑和地塞米松(R-GDP)、利妥昔單抗聯(lián)合卡氮芥、依托泊苷、阿糖胞苷、美法侖(R-BEAM)等[16, 18-24]。研究發(fā)現(xiàn)高劑量(1 000 mg/m2)R與標(biāo)準(zhǔn)劑量(375 mg/m2)比較,聯(lián)合BEAM序貫ASCT治療復(fù)發(fā)侵襲性B-NHL并不使患者顯著受益[25]。此外,ORCHARRD[26]研究比較Ofatumumab(人源IgG1k抗CD20單克隆抗體,與R的靶抗原表位不同)和R分別聯(lián)合DHAP-ASCT治療rr DLBCL的療效,結(jié)果表明O-DHAP 和R-DHAP作為挽救性化療方案,療效差異無(wú)統(tǒng)計(jì)學(xué)意義[27]。CORAL[18]研究比較R-DHAP和 R-ICE分別聯(lián)合HDC-ASCT治療侵襲性rr B-NHL(包括rr DLBCL)的療效,發(fā)現(xiàn)R-ICE和R-DHAP的總緩解率(ORR)、3年無(wú)事件生存率(EFS)和OS差異均無(wú)統(tǒng)計(jì)學(xué)意義。隨后的研究進(jìn)行亞組分析發(fā)現(xiàn)R-DHAP優(yōu)于R-ICE可改善GCB-DLBCL患者的預(yù)后[28-29]。目前搶救性化療和移植預(yù)處理方案仍然不理想,最佳方案仍有待確定[9, 17]。

    對(duì)R-CHOP等方案耐藥的rr DLBCL,后續(xù)使用前期化療方案極可能是無(wú)效的,甚至對(duì)多種化療藥物交叉耐藥[30-31]。盡管給予挽救性化療和ASCT等,許多患者最終仍死于惡性腫瘤,3年OS僅為30%[29,32]。此外,雖然異基因造血干細(xì)胞移植(allo-HSCT)為治愈淋巴瘤提供了可能,但由于移植相關(guān)死亡率高,這種治療策略可能對(duì)患者造成極大的負(fù)面影響。因此,rr DLBCL患者唯一可行的是參與臨床試驗(yàn),用新的試驗(yàn)性藥物或方法進(jìn)行治療[29, 32]。

    2 新藥物的應(yīng)用

    rr DLBCL耐藥機(jī)制可分為以下3種:①先天性耐藥,腫瘤細(xì)胞遺傳學(xué)異質(zhì)性,耐藥與重現(xiàn)性基因突變和基因異常表達(dá)有關(guān)[33];②獲得性耐藥,經(jīng)過(guò)前期化療藥物篩選,腫瘤細(xì)胞遺傳學(xué)和表觀遺傳學(xué)不穩(wěn)定,耐藥腫瘤克隆亞群出現(xiàn),最終導(dǎo)致標(biāo)準(zhǔn)方案化療失敗[34-35];③腫瘤細(xì)胞微環(huán)境/細(xì)胞黏附介導(dǎo)耐藥,源于腫瘤細(xì)胞與正常基質(zhì)組織之間的相互作用[36-38]。由于DLBCL遺傳學(xué)異質(zhì)性,多重耐藥分子機(jī)制在rr DLBCL耐藥中發(fā)揮作用。研究者從分子機(jī)制、相關(guān)信號(hào)通路等出發(fā),試圖通過(guò)新藥干預(yù)腫瘤細(xì)胞代謝、增殖、生長(zhǎng)等,進(jìn)而達(dá)到治療目的。

    2.1信號(hào)通路抑制劑

    2.1.1B細(xì)胞抗原受體(BCR)信號(hào)通路抑制劑 慢性活化BCR介導(dǎo)信號(hào)被認(rèn)為在ABC-DLBCL發(fā)病機(jī)制中扮演重要角色[39-40],而其主要依賴于布魯頓酪氨酸激酶(BTK),脾酪氨酸激酶(SYK)和磷酸肌醇3-激酶(PI3K)[41]。研究發(fā)現(xiàn)在rr ABC-DLBCL中BTK,SYK和PI3K激酶異?;罨痆39-40]。SYK或BTK的siRNA和小分子抑制劑可以選擇性抑制BCR信號(hào),并誘導(dǎo)依賴于BCR信號(hào)的DLBCL細(xì)胞系凋亡[42-45]。 Ibrutinib是一種選擇性、不可逆的BTK抑制劑[46]。一項(xiàng)Ibrutinib(PCI-32765)治療80例rr DLBCL患者的Ⅰ/Ⅱ臨床試驗(yàn)表明:其在ABC亞型中ORR為37%,CR率為16%;而在GCB亞型中治療反應(yīng)較差[47-49]。因此,Ibrutinib作用局限于BCR信號(hào)持續(xù)活化ABC-DLBCL[47, 50-51]。值得注意的是,Ibrutinib并沒(méi)有抑制BCR野生型且具有MyD88和(或)CARD11突變的腫瘤細(xì)胞生長(zhǎng)和存活,表明Ibrutinib特異性靶向作用有賴于慢性活化的BCR信號(hào)[50-51]。

    Fostamatinib(R406,F(xiàn)osD)為選擇性口服小分子SYK抑制劑,一項(xiàng)Ⅰ/Ⅱ研究中,超過(guò)20%的患者為多次rrDLBCL,使用fostamatinib治療后CR僅為5%[52]。一項(xiàng)Ⅱ期研究報(bào)告68例rr DLBCL患者接受fostamatinib治療,結(jié)果表明雙臂ORR為3%,13%患者臨床受益(≥疾病穩(wěn)定),而受益者主要集中在GCB亞型(4例),沒(méi)有1例是ABC亞型[53]。雖然患者對(duì)fostamatinib表現(xiàn)出良好的耐受性,但療效卻差強(qiáng)人意,與其他BCR通路抑制劑不同,在ABC亞型中沒(méi)有觀察到治療反應(yīng)[53]。

    2.1.2蛋白激酶Cβ(PKCβ)抑制劑 PKCβ Ⅱ是一種絲氨酸/蘇氨酸激酶亞型,通過(guò)BCR信號(hào)通路擴(kuò)增在rr DLBCL中高表達(dá),而PKCβ Ⅱ過(guò)表達(dá)與同源性磷酸酶-張力蛋白(PTEN)缺失引起的不良預(yù)后相關(guān),被認(rèn)為是潛在治療靶點(diǎn)[54-56]。研究表明PKCβⅡ的兩種選擇性抑制劑-sotrastaurin(AEB071)和enzastaurin,在體內(nèi)外試驗(yàn)可以誘導(dǎo)ABC-DLBCL細(xì)胞凋亡和抑制增殖[57-58]。目前一項(xiàng)評(píng)估sotrastaurin治療具有CD79A或CD79B突變的rr DLBCL的國(guó)際多中心I期臨床研究正在進(jìn)行中[59]。一項(xiàng)納入55例rr DLBCL的Ⅱ期研究顯示,患者每日接受enzastaurin治療直至疾病進(jìn)展或出現(xiàn)不可耐受的毒性。其中12例經(jīng)過(guò)2周期治療獲得無(wú)進(jìn)展(FFP),4例實(shí)現(xiàn)超過(guò)20個(gè)月FFP[60-61]。另一項(xiàng)隨機(jī)Ⅱ期研究初步結(jié)果顯示在100例中高危DLBCL患者,enzastaurin聯(lián)合R-CHOP治療可有效提高PFS(聯(lián)合用藥與單用R-CHOP,1年P(guān)FS分別為71%,52%)[62],但enzastaurin單藥治療rr DLBCL的療效卻十分有限[60-61, 63]。

    2.1.3Toll樣受體拮抗劑 在DLBCL中,MyD88是NF-κB信號(hào)通路中是一個(gè)適配轉(zhuǎn)導(dǎo)蛋白,可與 Toll樣受體(TLRs)7、8和9相互作用[64]。MyD88異??苫罨疶LRs, 激活信號(hào)通路促進(jìn)腫瘤細(xì)胞存活和增殖。TLR拮抗劑能直接抑制TLR/MyD88信號(hào)通路,克服MyD88突變的BCR野生型ABC-DLBCL對(duì)Ibrutinib耐藥[65]。IMO-8400是一個(gè)設(shè)計(jì)的拮抗寡核苷酸,在DLBCL細(xì)胞系中抑制MyD88-L265P配體活化,進(jìn)而抑制腫瘤細(xì)胞生存和增殖,為臨床評(píng)估提供科學(xué)依據(jù)[66]。

    2.1.4蛋白酶體抑制劑 在ABC-DLBCL中,bortezomib、carfilzomib等蛋白酶體抑制劑可以阻滯細(xì)胞周期負(fù)性調(diào)控因子和NF-κB抑制蛋白IκBα的降解,從而誘導(dǎo)細(xì)胞周期阻滯和線粒體依賴性凋亡[67-68]。Bortezomib聯(lián)合(R)CHOP和DA-EPOCH化療,可以靶向抑制NF-κB通路并選擇性地對(duì)rr ABC-DLBCL有效,而對(duì)GCB亞型作用微乎其微[69]。Bortezomib單藥治療無(wú)明顯活性,但聯(lián)合其他藥物可顯著提高治療反應(yīng)(ABC型和GCB型分別為83%、13%)和延長(zhǎng)生存期(中位OS分別是10.8、3.4個(gè)月)[69-71]。并非所有的ABC-DLBCL都對(duì)bortezomib敏感,蛋白酶體抑制劑不僅觸發(fā)促凋亡蛋白積累,也可上調(diào)抗MCL1[72]、HSP90[73]等凋亡蛋白,導(dǎo)致bortezomib耐藥。

    2.1.5JAK2/STAT3抑制劑 在rr ABC-DLBCL中,JAK激酶/信號(hào)轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子3(JAK/STAT3)信號(hào)通路是另一種潛在治療藥物靶點(diǎn),STAT3活化與R-CHOP治療后不良OS相關(guān)[74]。臨床級(jí)JAK1和JAK2口服抑制劑 fedratinib(SAR302503/TG101348)或ruxolitinib可以阻礙STAT1和STAT3磷酸化,被提議進(jìn)行臨床評(píng)估[75-77]。 此外,新型JAK2/JAK2(V617F)選擇性口服抑制劑-pacritinib(SB1518)阻斷STAT1、STAT3和STAT5磷酸化,建議在rr DLBCL患者中進(jìn)一步研究[77-78]。I期劑量與藥代動(dòng)力學(xué)/藥效學(xué)研究顯示pacritinib(SB1518)治療rr B-NHL的安全性和活性,為靶向治療淋巴瘤提供證據(jù)[77-79]。不幸的是,并未在5例rr DLBCL患者中觀察到治療反應(yīng),不除外是由于樣本量小造成的[77-79]。到目前為止,pacritinib(SB1518)是第一個(gè)也是唯一個(gè)在rr DLBCL患者中評(píng)估的JAK2抑制劑[77]。

    2.1.6PI3K/AKT/mTORC1通路抑制劑 PI3K/AKT/mTORC1通路活化在GCB-DLBCL腫瘤細(xì)胞生存和化療耐藥中發(fā)揮核心作用,是治療rr GCB-DLBCL的潛在目標(biāo)[80]。Idelalisib(GS-1101 、CAL-101)是一種PI3K同型體p110δ的選擇性可逆口服抑制劑,目前開(kāi)展多項(xiàng)I期臨床試驗(yàn)用于評(píng)估單藥和聯(lián)合用藥治療rr DLBCL安全性和有效性[81]。

    2.2免疫調(diào)節(jié)藥物 研究證明lenalidomide可以優(yōu)先抑制ABC-DLBCL細(xì)胞的增殖和存活,而對(duì)GCB亞型影響非常小[42, 82]。lenalidomide治療rr DLBCL患者,ABC亞型(ORR為52.9%)比GCB亞型(ORR為8.7%)治療反應(yīng)更好[83]。多個(gè)Ⅰ/Ⅱ臨床試驗(yàn)顯示lenalidomide單藥治療rr ABC-DLBCL反應(yīng)持久(ORR高達(dá)53%,CR高達(dá)23%)[83-87]。一項(xiàng)隨機(jī)多中心、開(kāi)放標(biāo)簽、2/3期臨床研究比較lenalidomide單藥與研究者選擇單藥(IC:吉西他濱、R、依托泊苷、奧沙利鉑)治療rr DLBCL的療效和安全性,結(jié)果表明lenalidomide單藥治療更安全有效(lenalidomide與IC的ORR分別為27.5%和11.8%;中位PFS分別為13.6周和7.9周),rr ABC-DLBCL顯著獲益(ABC亞型和GCB亞型的ORR分別為45.5%、21.4%,PFS分別為82周、13.2周;OS分別為108.4周、30周)[88]。

    Hagner等[89]研究發(fā)現(xiàn)CC-122是一種類(lèi)似于沙利度胺的新型免疫調(diào)節(jié)藥物,能直接與E3泛素酶復(fù)合物受體蛋白cereblon(CRBN)結(jié)合,在體外、體內(nèi)實(shí)驗(yàn)和rr DLBCL患者中促進(jìn)泛素化和Aiolos及Ikaros降解,通過(guò)直接抑制干擾素刺激基因(ISGs)轉(zhuǎn)錄和誘導(dǎo)干擾素誘導(dǎo)蛋白,導(dǎo)致DLBCL細(xì)胞凋亡。CC-122區(qū)別于沙利度胺類(lèi)似物家族成員,不受細(xì)胞起源限制,對(duì)ABC亞型和GCB亞型均有抗瘤活性,與Len僅對(duì)ABC亞型具有選擇性作用形成鮮明對(duì)比[89]。因此,CC-122被認(rèn)為是一種多效性途徑修飾新型藥物,彌補(bǔ)Len不足,對(duì)GCB-DLBCL有潛在治療活性[89-90]。

    2.3組蛋白去乙?;嚓P(guān)藥物 研究發(fā)現(xiàn)組蛋白去乙?;?HDAC)小分子抑制劑可作為潛在的藥物治療rr DLBCL[91]。HDAC抑制劑(HDACi)通過(guò)多個(gè)機(jī)制作用于GCB和ABC-DLBCL[91-92],部分HDACi已經(jīng)批準(zhǔn)用于臨床或臨床試驗(yàn)[93]。去乙?;负头篐DACi可協(xié)同殺死DLBCL,尤其是GCB-DLBCL,其治療rr NHL的ORR為18%、CR為18%,46%患者達(dá)到疾病穩(wěn)定狀態(tài)[94];其他HDACi(vorinostatromidepsin, panobinostat, mgc0103等)單用或與聯(lián)合用藥治療rr DLBCL同樣取得令人鼓舞的效果[95]。

    2.4單克隆抗體

    2.4.1程序性死亡受體(PD) 抗體PD-1是表達(dá)于T細(xì)胞表面的抑制性受體,配體PD-L1和PD-L2表達(dá)于抗原呈遞細(xì)胞,受體配體結(jié)合后限制T細(xì)胞的活化和增殖[96]。PD-L1在10%~14%DLBCL-NOS中異常高表達(dá)提示預(yù)后更差[97-99]。一項(xiàng)Ⅱ期臨床研究使用抗PD-1抗體pidilizumab治療ASCT后rr DLBCL,結(jié)果顯示ORR為51%,ASCT后仍有殘留病的患者的CR率達(dá)34%;16個(gè)月的PFS為72%,高危患者PFS為70%[100]。這些數(shù)據(jù)表明PD-1是一個(gè)治療rr DLBCL的理想靶標(biāo)。一項(xiàng)評(píng)估抗PD-1抗體單藥治療rr DLBCL的Ⅱ期臨床試驗(yàn)正在進(jìn)行中,此外,抗PD-1抗體聯(lián)合其他藥物治療的臨床試驗(yàn)也在開(kāi)展[98]。

    2.4.2抗體化學(xué)毒素偶聯(lián)物(ADCs) ADCs將細(xì)胞毒性藥物與腫瘤抗原的特異性抗體結(jié)合,是治療侵襲性B-NHL的新藥物,目前主要分子目標(biāo)是CD19、CD22、CD30等[101-102]。SAR3419是抗CD19抗體與細(xì)胞毒美登素DM4偶聯(lián)ADC,1個(gè)潛在的微管蛋白聚合和微管組裝抑制劑[101-102]。兩個(gè)Ⅰ期臨床研究評(píng)估SAR3419治療rr DLBCL的安全性和藥代動(dòng)力學(xué),發(fā)現(xiàn)SAR3419可以安全地用于治療rr DLBCL[103-104]。SGN-CD19A是另一個(gè)抗CD19特異性ADC,I期研究中期分析顯示其對(duì)rr DLBCL具有良好的治療反應(yīng)(ORR為35%,CR為20%,PR為16%),在rr DLBCL中更高(ORR為55%,CR為32%,PR為23%)[105-106]。

    Inotuzumab-ozogamicin是一個(gè)親和優(yōu)化單克隆抗CD22抗體與DNA損傷的毒素N-乙酰-γ-卡奇霉素-二酰肼(CalichDMH)偶聯(lián)ADC[107],其治療反應(yīng)ORR可達(dá)40%~74%,CR可達(dá)21%~50%[108]。Brentuximab-vedotin是一種人類(lèi)CD30特異性ADC[101],大約20%~30% DLBCL表達(dá)CD30,而在ABC-DLBCL中表達(dá)頻率更高[109-110]。Brentuximab-vedotin單藥治療CD30+ rr DLBCL,ORR為44%,CR為17%,截止報(bào)道時(shí)中位OS為16.6個(gè)月[111]。Polatuzumab-vedotin是一個(gè)抗CD79B的ADC[101]。Polatuzumab-vedotin治療rr DLBCL,ORR為56%和CR為14.8%[112-113]。

    此外,EZH2抑制劑GSK-126[114]、CPI-360[115]等,BRD4(和BRD2)抑制劑OTX015[116]等, BCL6抑制劑PU-H71[117]等,靶向作用于BCL2、BFL-1和MCL1等凋亡蛋白的小分子BH3類(lèi)似物ABT-737, ABT-199[118-119]等,涌現(xiàn)的新藥在rr DLBCL體內(nèi)外實(shí)驗(yàn)中具有潛在抗腫瘤活性,仍需在臨床實(shí)驗(yàn)中進(jìn)一步驗(yàn)證。

    3 嵌合抗原受體(CAR)T細(xì)胞治療

    CART細(xì)胞治療最早用于2例復(fù)發(fā)/難治性急性淋巴細(xì)胞白血病患者,治療后獲得持久CR[120]。CART細(xì)胞治療是通過(guò)基因工程T細(xì)胞識(shí)別并結(jié)合特異性腫瘤相關(guān)抗原,經(jīng)信號(hào)轉(zhuǎn)導(dǎo)途徑激活T細(xì)胞,釋放顆粒酶、穿孔素及多種細(xì)胞因子引發(fā)腫瘤細(xì)胞凋亡,從而發(fā)揮抗腫瘤效應(yīng),目前最常見(jiàn)的靶標(biāo)為CD19、CD20等。

    2015年美國(guó)國(guó)家癌癥研究所(NCI)第一次在DLBCL中證實(shí)抗CD19 CART的抗瘤活性,該研究中11例rr B-NHL患者進(jìn)行FC方案預(yù)處理后輸注MC63-28Z CART細(xì)胞[121]。其中4例rr DLBCL患者2例達(dá)到CR[121]。賓夕法尼亞大學(xué)的數(shù)據(jù)證實(shí)抗CD19 CART(CTL019)對(duì)多種rr NHL(包括DLBCL)具有顯著的抗瘤活性,12個(gè)月的ORR為68%和PFS為62%[122]。Turtle等[123]報(bào)道了32例B-NHL患者接受抗CD19 CART細(xì)胞治療,在所有亞型中都觀察到治療反應(yīng),ORR是63%,CR率是33%。 2017年NCI報(bào)道了22例rr B-NHL患者接受低劑量FC方案預(yù)處理之后輸注抗CD19 CART細(xì)胞治療[124]。研究發(fā)現(xiàn)在GCB和ABC亞型中均觀察到抗瘤活性,總體ORR為73%,CR為55%;rr DLBCL患者ORR為68%,CR為47%[124]。對(duì)于化療耐藥DLBCL,低劑量化療藥物不會(huì)產(chǎn)生明顯抗癌作用,據(jù)此,治療反應(yīng)可以肯定是由CART療法所致。更重要的是在這項(xiàng)研究中,CART細(xì)胞治療產(chǎn)生持久的緩解,在12例CR患者中11例持續(xù)緩解7~24個(gè)月;所有受試者12個(gè)月的PFS為63%[124]。CART治療主要的不良反應(yīng)是細(xì)胞因子釋放綜合征(CRS)和神經(jīng)系統(tǒng)毒性,55%的患者經(jīng)歷了3/4級(jí)的神經(jīng)系統(tǒng)疾病毒性,需要給予支持治療和重癥護(hù)理[124]。一種FMC63-28Z表達(dá)的CART細(xì)胞產(chǎn)品(和KTE-C19)指定為axicabtage neciloleucel,目前正在進(jìn)行商業(yè)化推廣[121, 124]。Locke等[125]評(píng)估了KTE-C19,自體CD3zζ/CD28-CAR T細(xì)胞治療難治性DLBCL?;颊呓邮艿蛣┝縁C方案預(yù)處理,隨后輸注KTE-C19(2×106CART/kg目標(biāo)劑量)[125]。研究結(jié)果顯示總體ORR為71%,CR率為57%,3例持續(xù)CR(12個(gè)月以上);7例接受治療的患者,1例出現(xiàn)4級(jí)CRS和神經(jīng)毒性,分別有1例和4例出現(xiàn)3級(jí)CRS和神經(jīng)毒性[125]。在隨后Ⅱ期多中心臨床研究中,101例侵襲性rr B-NHL接受axicabtage neciloleucel治療,初步結(jié)果顯示ORR是82%,CR率是54%;中位隨訪時(shí)間為8.7個(gè)月,ORR是44%,仍有39%患者持續(xù)CR[126-127]。

    一個(gè)多中心試驗(yàn)的JCAR017 抗CD19 CART產(chǎn)品治療rr B-NHL,研究表明在20例可評(píng)價(jià)的患者中,ORR為80%,CR率為60%[128]。Abramson等[129]報(bào)道了1例rr GCB-DLBCL老年女性,具有BCL2重排和MYC和BCL6多拷貝,經(jīng)過(guò)前期治療出現(xiàn)系統(tǒng)性和大腦右顳葉疾病復(fù)發(fā),接受JCAR017治療,藥代動(dòng)力學(xué)試驗(yàn)顯示CART細(xì)胞擴(kuò)增與腫瘤消退是一致的。對(duì)于系統(tǒng)性和中樞系統(tǒng)同步復(fù)發(fā)的患者來(lái)說(shuō),傳統(tǒng)治療的CR率很低(16%到22%),持久緩解十分罕見(jiàn)[130-131],該累及腦實(shí)質(zhì)的rr DLBCL患者通過(guò)JCAR017達(dá)到CR[129]。

    R成功治療B-NHL,突顯CD20是CART細(xì)胞治療的理想目標(biāo)。在一項(xiàng)研究中,2例DLBCL患者輸注第一代抗CD20 CART作為輔助治療,之后立即行ASCT,截止相關(guān)文章發(fā)表時(shí),1例患者獲得持續(xù)9年的CR,這是僅行ASCT難以實(shí)現(xiàn)的,另1例患者CR持續(xù)19 個(gè)月[132]。另一個(gè)臨床試驗(yàn)通過(guò)質(zhì)粒電穿孔轉(zhuǎn)染使T細(xì)胞表達(dá)第三代抗CD20 CART,預(yù)處理方案為環(huán)磷酰胺,后續(xù)3次CART細(xì)胞輸注,14天皮下注射白細(xì)胞介素2[133]。在細(xì)胞注入之前未評(píng)估的2例患者仍持續(xù)CR,1例達(dá)到客觀PR[133]。第3項(xiàng)研究通過(guò)慢病毒載體轉(zhuǎn)導(dǎo)使T細(xì)胞表達(dá)抗CD20的CAR和4-1BB共刺激域[134],該試驗(yàn)包括7例高強(qiáng)度預(yù)處理的DLBCL,隨后輸注逐漸增加細(xì)胞量的CART治療超過(guò)3~4天,5例患者有客觀反應(yīng),大多為PR,1例患者入組時(shí)為PR,之后獲得持續(xù)14個(gè)月的CR,不良事件包括CRS,延遲的腫瘤溶解,淋巴瘤侵及胃腸道導(dǎo)致消化道出血等[134]。雖然目前只獲得初步研究結(jié)果,但這些數(shù)據(jù)提示抗CD20 CART對(duì)B-NHL具有治療潛力。

    CART治療是一種快速發(fā)展的新興治療方式,能夠讓相當(dāng)比例rr B-NHL患者獲得持久CR。鑒于目前rr DLBCL治療方法非常有限,在沒(méi)有其他可行方法的時(shí)候,抗CD19 CART細(xì)胞治療誘導(dǎo)緩解能力可持續(xù)2~4年,因此CART治療rr DLBCL是淋巴瘤治療領(lǐng)域最重要發(fā)現(xiàn)。盡管目前該項(xiàng)治療仍有許多不足,但隨著CAR設(shè)計(jì)優(yōu)化、毒性改良、聯(lián)合用藥等會(huì)使CART細(xì)胞治療更加安全,使更多患者受益。

    綜上所述,盡管大多數(shù)DLBCL患者通過(guò)標(biāo)準(zhǔn)一線方案治療可達(dá)到并維持CR,但約30%患者可能經(jīng)歷疾病復(fù)發(fā)/難治,由于目前仍缺乏行之有效的治療手段,并且治療過(guò)程異常艱辛,rr DLBCL患者預(yù)后很差。隨著對(duì)疾病機(jī)制地進(jìn)一步研究,bortezomib, lenalidomide, CC122等新藥的合理干預(yù),CART治療方式引入等等,為改善此類(lèi)患者的不良預(yù)后提供了新思路和新方向。

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    Therapeuticprogressinrelapse/refractorydiffuselarge-B-celllymphoma

    Zhang Na, Gao Guangxun

    DepartmentofHematopathology,XijingHospitaloftheAirForeMedicalUniversity(FourthMilitaryMedicalUniversity),Xi′an710032,China

    GaoGuangxun,Email:gaoguangxun@fmmu.edu.cn

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous lymphoid malignancy and the most commonly occurring subtype of non-Hodgkin's lymphoma (NHL), with increasing incidence, which is great harmful to human health. More than 60% of DLBLC patients can be cured with standard R-CHOP regimens, however, approximately 30% of patients will develop relapsed/refractory disease that remains a major cause of mortality. With recent advances in gene expression profiling, the in-depth study of the molecular basis of chemotherapy resistance, optimization of salvage chemotherapy regimen, intervention of novel drugs and using chimeric antigen receptor T-cell therapy, and so on, these therapies might provide hope for individual accurate treatment of relapsed/refractory DLBCL. In this review, we focus on the progress of novel drugs and CART therapy in relapsed/refractory DLBCL.

    lymphoma, B-cell; recurrence; receptors, antigen, T-cell; therapy

    高廣勛,Email:gaoguangxun@fmmu.edu.cn

    R733.4

    A

    1004-583X(2017)12-1027-10

    10.3969/j.issn.1004-583X.2017.12.004

    2017-11-23 編輯:王秋紅

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