衛(wèi)治功王麗紅綜述 李平審校

·綜述·

免疫檢查點(diǎn)綜合治療策略的研究進(jìn)展

衛(wèi)治功①王麗紅①綜述 李平②審校

免疫治療的快速發(fā)展打破了手術(shù)、放化療以及靶向治療構(gòu)成的腫瘤常規(guī)治療模式。與傳統(tǒng)腫瘤治療相比，免疫治療的療效更持久，不良反應(yīng)更小。免疫檢查點(diǎn)抑制劑作為免疫治療的重要組成部分，在臨床前及臨床試驗(yàn)中已被證實(shí)具有廣闊的應(yīng)用前景。然而截至目前，這一療法所帶來(lái)的臨床獲益僅局限于部分腫瘤類型的少部分患者，因此需要合理的綜合治療策略克服這種局限?；虬邢蛑委?、放療、化療、腫瘤疫苗等都可以通過(guò)不同機(jī)制對(duì)免疫系統(tǒng)產(chǎn)生影響，為綜合治療提供了理論依據(jù)。本文就免疫檢查點(diǎn)治療及其與其他腫瘤治療方式聯(lián)合的綜合治療策略做一綜述。

免疫治療 免疫檢查點(diǎn) 共刺激分子 綜合治療策略

免疫細(xì)胞表面廣泛表達(dá)多種共信號(hào)分子，包括細(xì)胞毒T淋巴細(xì)胞相關(guān)抗原4（cytotoxic T-lympho?cyte-associated protein-4，CTLA-4）、程序性死亡受體1/程序性死亡配體1（programmed cell death protein-1/ligand-1，PD-1/L1）、淋巴細(xì)胞活化基因3（lympho?cyte-activation gene 3，LAG-3）、T細(xì)胞免疫球蛋白黏蛋白3（T cell immunoglobulin domain and mucin do?main-3，TIM-3）、B和T淋巴細(xì)胞弱化子（B-and T-lymphocyte attenuator，BTLA）、CD160等抑制性免疫檢查點(diǎn)分子，以及CD28、糖皮質(zhì)激素誘導(dǎo)的腫瘤壞死因子受體（glucocorticoid-induced TNFR-related protein，GITR）、OX40、CD27、CD40、4-1BB等共刺激分子［1］，這些分子與腫瘤微環(huán)境（tumor microenvironment，TME）中的復(fù)雜配體相互作用，調(diào)節(jié)抗腫瘤免疫應(yīng)答的最終效應(yīng)。TME中高表達(dá)的免疫檢查點(diǎn)分子可導(dǎo)致T細(xì)胞失能，是腫瘤免疫逃逸的重要機(jī)制之一。與傳統(tǒng)抗腫瘤治療模式不同，免疫檢查點(diǎn)抑制劑并不直接作用于腫瘤細(xì)胞，也不針對(duì)腫瘤表面的某些特定物質(zhì)，而是通過(guò)調(diào)節(jié)T細(xì)胞的活性，系統(tǒng)性增強(qiáng)全身抗腫瘤免疫。這一方法理論上講普遍有效，然而截至目前的臨床試驗(yàn)，單個(gè)免疫檢查點(diǎn)抑制劑的臨床獲益僅局限于部分患者。借助于放療、化療、靶向治療等傳統(tǒng)治療方式構(gòu)建或提高TME的免疫原性，或許可以使檢查點(diǎn)阻斷治療的療效變得更為廣泛、持久。隨著對(duì)抗腫瘤免疫應(yīng)答機(jī)制研究的深入，越來(lái)越多的綜合治療策略正在被評(píng)估中［2］。為了滿足個(gè)體化治療的需要，腫瘤治療的“雞尾酒療法”將會(huì)是今后腫瘤免疫治療研究的新方向［3］。

隨著抗CTLA-4、抗PD-1/L1抗體的成功，免疫檢查點(diǎn)抑制成為免疫治療的主要方法。CTLA-4表達(dá)于活化的CD4+和CD8+T細(xì)胞，通過(guò)阻斷T細(xì)胞抗原受體（T cell receptor，TCR）下游信號(hào)的傳導(dǎo)以及與CD28競(jìng)爭(zhēng)性結(jié)合配體從而負(fù)調(diào)節(jié)T細(xì)胞應(yīng)答。針對(duì)CT?LA-4的單克隆抗體ipilimumab是第一個(gè)被證實(shí)可以取得生存獲益的免疫檢查點(diǎn)抑制劑［4］，Ⅲ期臨床試驗(yàn)表明ipilimumab可以顯著提高進(jìn)展期黑色素瘤患者的總生存期。多個(gè)關(guān)于進(jìn)展期間皮瘤、胃癌、非小細(xì)胞肺癌（non-small cell lung cancer，NSCLC）、膀胱癌等的臨床試驗(yàn)正在評(píng)估抗CTLA-4抗體ipilimumab以及tremelimumab的療效［5］。PD-1主要表達(dá)在活化的T細(xì)胞、B細(xì)胞、樹(shù)突狀細(xì)胞（dendritic cells，DCs）表面。與CTLA-4類似，PD-1與配體結(jié)合后也可抑制TCR信號(hào)通路的下傳。針對(duì)PD-1/L1的阻斷性抗體在過(guò)去幾年也已經(jīng)進(jìn)入臨床階段，并且在轉(zhuǎn)移性黑色素瘤、肺癌、腎細(xì)胞癌中取得了廣泛的臨床獲益［3］。靶向于LAG-3、TIM-3等檢查點(diǎn)分子的抗體也正在研究中［6］。此外，T細(xì)胞的激活還需要共刺激分子的參與，靶向于GITR、4-1BB、OX-40以及CD40等共刺激分子的抗體可通過(guò)增強(qiáng)免疫細(xì)胞活性提高抗腫瘤免疫，在多種腫瘤的前期研究中也取得了不同程度的臨床療效［7-9］。

1 免疫檢查點(diǎn)抑制劑聯(lián)合治療

CTLA-4以及PD-1可調(diào)控不同的抑制性通路，研究證實(shí)，阻斷CTLA-4可以促進(jìn)T細(xì)胞進(jìn)入腫瘤組織成為腫瘤浸潤(rùn)淋巴細(xì)胞（tumor infiltrating lympho?cyte，TIL），TIL產(chǎn)生的細(xì)胞因子IFN-γ（interferon gam?ma）反過(guò)來(lái)具有誘導(dǎo)TME中PD-L1表達(dá)的作用［10］，從而增加患者從抗PD-1/L1治療中獲益的機(jī)會(huì)。在2015年報(bào)道的一項(xiàng)Ⅲ期臨床試驗(yàn)中，入組約1 000例不可切除的Ⅲ/Ⅳ期黑色素瘤患者，結(jié)果表明ipilim?umab聯(lián)合nivolumab治療組的中位無(wú)進(jìn)展生存期（median progression free survival，mPFS）為11.5個(gè)月，與ipilimumab或nivolumab單藥組相比分別提高8.6、4.6個(gè)月［11］?；诖搜芯棵绹?guó)食品藥品監(jiān)督管理局（food and drug administration，F(xiàn)DA）批準(zhǔn)ipilimumab聯(lián)合nivolumab用于進(jìn)展期黑色素瘤的治療。該聯(lián)合方案治療進(jìn)展期腎癌以及NSCLC的初期數(shù)據(jù)也顯示出較好的療效［12-13］。

2016年報(bào)道的一項(xiàng)Ⅰ期臨床試驗(yàn)評(píng)估了抗PD-1抗體MEDI0680聯(lián)合抗PD-L1抗體durvalumab治療的安全性及最大耐受劑量，初期數(shù)據(jù)表明該聯(lián)合方案耐受良好，在入組的30例不同類型的實(shí)體瘤患者中，臨床獲益率約為35%［14］。此外，動(dòng)物實(shí)驗(yàn)證實(shí)，PD-1及LAG-3可通過(guò)協(xié)同作用調(diào)節(jié)T細(xì)胞，增強(qiáng)腫瘤的免疫耐受。雙重阻斷治療可以抑制腫瘤生長(zhǎng)，促進(jìn)抗腫瘤免疫［15］。另一種抑制性受體TIM-3的阻斷劑在動(dòng)物模型中也被證實(shí)具有抗腫瘤活性，當(dāng)與抗PD-L1聯(lián)合應(yīng)用時(shí)這一作用更為明顯［16-17］。

2 免疫檢查點(diǎn)抑制聯(lián)合共刺激分子治療

免疫系統(tǒng)在腫瘤發(fā)展過(guò)程中是動(dòng)態(tài)變化的，不同共信號(hào)分子的表達(dá)調(diào)控也比較復(fù)雜，免疫檢查點(diǎn)及共刺激分子在免疫調(diào)節(jié)中的作用各有不同，且相互補(bǔ)充，聯(lián)合治療或許能增強(qiáng)抗腫瘤的療效［18］。共刺激分子OX-40具有促進(jìn)T細(xì)胞增殖、延長(zhǎng)T細(xì)胞生存的作用?？筄X-40的激動(dòng)性抗體聯(lián)合抗CTLA-4方案在動(dòng)物腫瘤模型中被研究證實(shí)可以顯著提高生存率［19］。在對(duì)單一治療無(wú)反應(yīng)的卵巢癌動(dòng)物模型中抗PD-1聯(lián)合抗OX-40可引起病灶消退［20］。另一種共刺激分子4-1BB的特異性抗體相關(guān)的臨床前研究中，抗4-1BB聯(lián)合CTLA-4阻斷、CD40活化或放射治療時(shí)均展現(xiàn)出一定的抗腫瘤活性［6］。

3 傳統(tǒng)抗腫瘤治療相關(guān)的綜合治療策略

3.1 基因靶向治療

基因靶向藥物對(duì)于含有特定基因突變的患者療效顯著，但耐藥性的產(chǎn)生導(dǎo)致緩解期相對(duì)短暫。與此相反，免疫檢查點(diǎn)抑制劑通過(guò)作用于單一靶點(diǎn)，可潛在地釋放針對(duì)多種不同腫瘤抗原的T細(xì)胞，從而產(chǎn)生持久應(yīng)答［21］。聯(lián)合治療或許能夠綜合兩種療法的優(yōu)勢(shì)，產(chǎn)生更為廣泛和持久的臨床獲益?；虬邢蛑委熗ㄟ^(guò)殺傷腫瘤細(xì)胞，導(dǎo)致腫瘤抗原以及新生抗原的釋放，這些抗原隨后被抗原提呈細(xì)胞（antigen presenting cells，APCs）提呈給腫瘤特異性T細(xì)胞，誘導(dǎo)其活化，同時(shí)上調(diào)CTLA-4、PD-1等表達(dá)，增加檢查點(diǎn)抑制劑的作用靶點(diǎn)，從而提高免疫治療療效。此外靶向治療釋放的腫瘤抗原還可以使檢查點(diǎn)抑制劑產(chǎn)生的免疫反應(yīng)更為集中，從而減輕不良反應(yīng)［22］。

一項(xiàng)表皮生長(zhǎng)因子受體（epidermal growth factor receptor，EGFR）抑制劑erlotinib聯(lián)合抗PD-1抗體nivolumab治療晚期NSCLC的研究表明，聯(lián)合用藥是克服靶向耐藥的一項(xiàng)選擇［23］。治療黑色素瘤的BRAF抑制劑vemurafenib被證實(shí)可以提高腫瘤抗原以及MHC分子的表達(dá)，使得腫瘤細(xì)胞更易于被免疫系統(tǒng)攻擊［24］。然而并非所有研究都取得了期望中的結(jié)果，一項(xiàng)關(guān)于vemurafenib聯(lián)合ipilimumab的臨床試驗(yàn)由于嚴(yán)重的肝毒性而終止［25］。另一項(xiàng)BRAF抑制劑dabrafenib聯(lián)合ipilimumab的臨床試驗(yàn)則表現(xiàn)出較好的耐受性［26］。類似的情況也出現(xiàn)在酪氨酸激酶抑制劑sunitinib聯(lián)合不同的檢查點(diǎn)抑制劑治療轉(zhuǎn)移性腎癌的研究中［27-28］。上述結(jié)果表明在評(píng)估聯(lián)合治療方案時(shí)，藥物種類、劑量和（或）給藥周期等均需給予特別關(guān)注。

3.2 放療

放療對(duì)免疫系統(tǒng)同樣存在多方面的影響。研究表明，放療可以誘導(dǎo)或增強(qiáng)所有階段的T細(xì)胞應(yīng)答，包括T細(xì)胞激活、轉(zhuǎn)移以及在腫瘤內(nèi)的應(yīng)答等?？赡艿臋C(jī)制包括：促進(jìn)腫瘤抗原的釋放、攝取以及DCs的交叉提呈，促進(jìn)誘導(dǎo)T細(xì)胞及DCs聚集的促炎因子以及趨化因子的產(chǎn)生等［22］。

在臨床前研究中，局部放療聯(lián)合系統(tǒng)性CTLA-4或PD-1阻斷治療可抑制腫瘤轉(zhuǎn)移［29-30］。動(dòng)物模型及部分臨床個(gè)案證實(shí)，在給予系統(tǒng)性抗CTLA-4治療的基礎(chǔ)上，局部放療不僅可以導(dǎo)致已照射區(qū)的腫瘤消退，還可引起遠(yuǎn)處病灶生長(zhǎng)延遲甚至消退［31］。這一方案在治療去勢(shì)抵抗型前列腺癌的試驗(yàn)中也表現(xiàn)出抗腫瘤活性［32］。此外，共刺激因子OX40抗體被證實(shí)與高劑量局部放療具有協(xié)同作用［33］。大量放療相關(guān)聯(lián)合方案的臨床試驗(yàn)正在開(kāi)展中，將會(huì)對(duì)未來(lái)的研究提供更多有價(jià)值的信息［34］。與放療類似，冷凍療法等其他腫瘤局部治療方式也可誘導(dǎo)抗原釋放以及局部免疫應(yīng)答。在動(dòng)物模型中對(duì)原發(fā)腫瘤行冷凍消融術(shù)聯(lián)合系統(tǒng)CTLA-4阻斷，同樣可以抑制遠(yuǎn)處病灶的生長(zhǎng)［35-36］。

3.3 化療

大部分化學(xué)治療藥物在直接殺傷腫瘤細(xì)胞的同時(shí)，也將通過(guò)骨髓抑制等機(jī)制導(dǎo)致免疫細(xì)胞的減少，因此化療聯(lián)合免疫治療似乎是違反常理的。然而，多項(xiàng)研究證實(shí)，化療也可對(duì)免疫系統(tǒng)產(chǎn)生積極影響?；熣T導(dǎo)的腫瘤細(xì)胞免疫原性死亡可導(dǎo)致腫瘤抗原高表達(dá)，隨后通過(guò)活化DCs產(chǎn)生抗腫瘤應(yīng)答［37］。此外，化療藥物還可以通過(guò)影響共信號(hào)分子表達(dá)，消耗負(fù)性免疫調(diào)節(jié)蛋白等方式，擾亂腫瘤的免疫逃避機(jī)制［38］。上述研究結(jié)果為化療聯(lián)合免疫檢查點(diǎn)治療提供了可能。大量臨床前研究評(píng)估了不同化療藥物聯(lián)合免疫檢查點(diǎn)抑制劑的療效［39-40］。一項(xiàng)ipilimumab聯(lián)合PC方案（紫杉醇+卡鉑）治療晚期NSCLC的Ⅱ期臨床試驗(yàn)結(jié)果證實(shí)了該方案的可行性［41］。而niv?olumab聯(lián)合鉑類為基礎(chǔ)的化療方案則表現(xiàn)出不良反應(yīng)的增加［42］。其他涉及抗PD-1/L1抗體的聯(lián)合方案也正在評(píng)估當(dāng)中［37］。在共刺激分子激動(dòng)劑聯(lián)合化療的方案中，抗CD40抗體CP-870、CP-893聯(lián)合吉西他濱治療進(jìn)展期胰腺癌的試驗(yàn)表現(xiàn)出較好的臨床反應(yīng)［43］。同樣的抗體聯(lián)合卡鉑以及紫杉醇的研究也被證實(shí)具有免疫活化的作用［44］。

3.4 腫瘤疫苗

同免疫檢查點(diǎn)治療類似，抗腫瘤疫苗通過(guò)活化適應(yīng)性免疫應(yīng)答，誘導(dǎo)機(jī)體的抗腫瘤免疫。由于腫瘤的免疫逃逸以及抑制性免疫環(huán)境的存在，使得腫瘤疫苗的研究和應(yīng)用相對(duì)困難。免疫檢查點(diǎn)抑制劑通過(guò)打破免疫抑制微環(huán)境，影響腫瘤的免疫耐受，從而使腫瘤疫苗充分發(fā)揮作用［45］。另一方面，腫瘤疫苗也可活化外周T細(xì)胞，促進(jìn)其浸潤(rùn)至腫瘤組織，從而誘導(dǎo)抗腫瘤免疫以及增強(qiáng)抗PD-1/L1治療的療效。此外，與抗CTLA-4聯(lián)合抗PD-1/L1相比，疫苗相關(guān)的聯(lián)合方案并未顯著增加不良反應(yīng)［46］。

一項(xiàng)Ⅲ期臨床試驗(yàn)評(píng)估了多肽疫苗GP100聯(lián)合ipilimumab用于進(jìn)展期黑色素瘤的治療，然而并未觀察到額外獲益［47］，原因尚不明確。DC疫苗聯(lián)合抗CTLA-4阻斷在不同的動(dòng)物模型中被證實(shí)比單一治療更為有效［2］。由APCs制備的Sipuleucel-T（Provenge）用于難治性前列腺癌的治療中，病理學(xué)證實(shí)經(jīng)Sipuleucel-T治療的前列腺癌組織中出現(xiàn)了TIL的增加以及PD-1表達(dá)［48］。相關(guān)臨床試驗(yàn)正在評(píng)估此類疫苗聯(lián)合抗PD-1抗體的療效（NCT01420965）。此外部分臨床前試驗(yàn)還證實(shí)了經(jīng)修飾的同源腫瘤細(xì)胞疫苗、病毒載體疫苗與免疫檢查點(diǎn)抑制劑具有協(xié)同作用［2］。

3.5 溶瘤病毒

經(jīng)基因修飾的溶瘤病毒可以選擇性地在腫瘤細(xì)胞內(nèi)復(fù)制，導(dǎo)致細(xì)胞溶解及死亡，同時(shí)釋放腫瘤抗原，刺激機(jī)體免疫應(yīng)答［49］。用于黑色素瘤瘤內(nèi)注射的Talimogene laherparepvec（T-vec）是轉(zhuǎn)染GM-CSF的基因重組單純皰疹病毒，T-vec聯(lián)合抗CTLA-4［50］或抗PD-1［51］的臨床試驗(yàn)正在開(kāi)展，初步數(shù)據(jù)顯示出較好的療效。enadenotucirev是一種可以系統(tǒng)性給藥的溶瘤腺病毒療法，其聯(lián)合抗PD-1抗體pembroli?zumab的臨床試驗(yàn)［52］已被報(bào)道。

4 總結(jié)與展望

免疫檢查點(diǎn)抑制劑在越來(lái)越多的腫瘤中被證實(shí)具有較好的療效。同時(shí)，也需要合理的綜合治療策略使其適用于更多的患者和更廣的腫瘤類型。盡管這種治療方案前景廣闊，但是在其應(yīng)用潛力發(fā)揮和廣泛臨床推廣之前，還有許多難題亟待解決。在已經(jīng)過(guò)驗(yàn)證或正在研究的治療策略中，有很多不僅是無(wú)效的，而且會(huì)增加不良反應(yīng)，綜合治療的藥物種類，給藥劑量、周期以及次序等均會(huì)對(duì)臨床療效產(chǎn)生影響。此外在缺乏可靠的預(yù)測(cè)性生物標(biāo)記物的情況下，免疫治療的療效還受到包括腫瘤的組織學(xué)類型、患者之間的變異，甚至是同一患者腫瘤內(nèi)的異質(zhì)性等多種因素影響。了解腫瘤、免疫系統(tǒng)以及不同治療方案之間的相互作用機(jī)制，將有助于設(shè)計(jì)出更多新型、有效、合理的腫瘤綜合治療策略。

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（2017-03-10收稿）

（2017-04-26修回）

（編輯：孫喜佳 校對(duì)：鄭莉）

Comprehensive therapeutic strategies regarding immune checkpoint

Zhigong WEI1,Lihong WANG1,Ping LI2

Ping LI;E-mail:leepingmd68@vip.163.com
1West China School of Medicine,Sichuan University,Chengdu 610000,China;2No.1 Department of Oncology,West China Hospital,Sichuan University,Chengdu 610000,China

The rapid development of immunotherapy has exceeded that of standard treatment modes,which include surgery,radiotherapy,chemotherapy,and targeted therapy.Immunotherapy is more durable and less toxic than traditional cancer therapies.Moreover,immune checkpoint therapy is an important component of immunotherapy and has been evaluated in preclinical and clinical trials and proven to exhibit broad prospects.However,its clinical benefits are limited to a small subset of patients with a subset of tumor types.Therefore,reasonable comprehensive therapeutic strategies are needed to overcome this limitation.Gene targeted therapy,radiotherapy,chemotherapy,and tumor vaccine affect the immune system through different mechanisms,and these could provide theoretical bases for comprehensive treatments.In this review,immune checkpoint therapy and its potential comprehensive therapies with other cancer treatments are introduced.

immunotherapy,immune checkpoint,costimulatory molecule,comprehensive therapeutic strategies

10.3969/j.issn.1000-8179.2017.15.270

①四川大學(xué)華西臨床醫(yī)學(xué)院（成都市610000）；②四川大學(xué)華西醫(yī)院腫瘤一科

李平leepingmd68@vip.163.com

衛(wèi)治功專業(yè)方向?yàn)槟[瘤放射治療學(xué)。

E-mail：839508967@qq.com