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T细胞免疫治疗实体肿瘤的临床试验疗效分析
我爱萨其马虞co 发表于:2021-7-20 09:29:14 复制链接 看图 发表新帖
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本文泉源:
国际免疫学杂志, 2021,44(01)
: 51-58.


DOI:
10.3760/cma.j.issn.1673-4394.2021.01.009

本文引用:
母松, 李子林, 金艾顺. T细胞免疫治疗实体肿瘤的临床试验疗效分析 [J] .



T细胞免疫治疗实体肿瘤的临床试验疗效分析
择要
过继性T细胞治疗(adoptive cell transfer therapy,ACT)是以肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)、基因工程编辑的T细胞受体T细胞(T cell receptor engineered T cells,TCR-T)和嵌合抗原受体T细胞(chimeric antibody receptor engineered T cell,CAR-T)为主的特异性细胞免疫治疗本领。现在TIL和TCR-T疗法,尤其是TIL和TCR-T团结其他方案如白细胞介素(interleukin,IL )-2、步调性殒命受体1(programmed death-1,PD-1)抗体、放疗等在部门晚期实体肿瘤患者的临床试验中取得明显疗效,但干系研究尚处于临床前研究阶段,现就TIL和TCR-T疗法治疗实体肿瘤的临床疗效及常见不良反应的研究希望做一综述。


恶性肿瘤的治疗恒久以来因疗效差、肿瘤复发、转移及不良反应等题目成为环球性困难,尤其是晚期实体肿瘤。过继性T细胞治疗(adoptive cell transfer therapy,ACT)是将具有抗肿瘤活性的T细胞回输至患者体内发挥抗肿瘤免疫效应的一种新疗法,在部门晚期实体肿瘤临床试验中取得明显疗效。将肿瘤中浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)分离并扩增回输至患者体内,观察到肿瘤差异程度的消退,以致有"治愈"的病例[1,2,3],体现了TIL疗法在治疗晚期实体肿瘤中巨大潜力。随着对T细胞抗肿瘤作用熟悉的深入,基因编辑的T细胞受体T细胞(T cell receptor engineered T cells,TCR-T)疗法在部门实体肿瘤治疗中亦显现出较好的抗肿瘤本领[4,5]。文章团结现在已开展或正在开展临床实验研究,就TIL和TCR-T疗法治疗实体肿瘤的临床疗效及常见不良反应的研究希望做一综述。


1
TIL疗法治疗实体肿瘤的临床试验疗效分析TIL为肿瘤微情况中天然存在的浸润淋巴细胞,细胞分类重要以T细胞为主。TIL疗法就是将患者肿瘤构造中浸润淋巴细胞在体外经高剂量白细胞介素(interleukin,IL )-2激活扩增,通过筛选这部门具有抗肿瘤活性的反应性T细胞回输到患者体内发挥抗肿瘤的作用[6,7]。研究发现,通过团结TIL与其他方案治疗肿瘤不光可以进步治疗效果,同时也可低落不良反应发生率,对肿瘤的临床治疗有着紧张意义。
1.1 TIL疗法团结IL-2治疗

IL-2作为一种T细胞生长因子,可以大概刺激T细胞进入细胞分裂周期并增强T细胞的杀伤活性,从而发挥抗肿瘤的生物学作用[8]。研究表明仅用IL-2治疗具有肯定的抗肿瘤作用,但高剂量的IL-2引起的毒副作用不容忽视[9]。TIL团结高剂量IL-2(720 000 IU/kg·8h)治疗观察到客观缓解率为31%[10],表明团结高剂量的IL-2治疗可进步TIL治疗疗效。别的,对转移性玄色素瘤患者接纳皮下注射低剂量IL-2(2 MIU/d),观察到33%患者出现完全缓解[11]。Andersen等[12]接纳IL-2剂量递减方案团结TIL治疗,效果体现患者客观缓解率为42%。由此表明,TIL团结高剂量IL-2并不是TIL治疗临床获益的绝对条件,低剂量IL-2的改良方案同样可以大概取得较好的客观缓解率,且明显镌汰了高剂量IL-2产生的不良反应。
一项II期临床试验体现,在TIL和IL-2输注前加用环磷酰胺和氟达拉滨,可将TIL治疗的客观缓解率进步到51%[13],提示TIL团结IL-2治疗前对内源性淋巴细胞扫除性处理处罚可以大概明显增强抗肿瘤作用,其机制大概与低落了内源性淋巴细胞与TIL的竞争作用及镌汰了体内调治性T细胞的数目有关[13,14]。因此,确保回输T细胞在体内的恒久性和排除免疫微情况克制作用对进步T细胞治疗的疗效发挥着紧张作用。
1.2 TIL疗法团结放射治疗

局部放射治疗不光可以直接引起肿瘤细胞损伤,也可以大概间接改变肿瘤的微情况。研究表明,局部放射可以通过进步肿瘤细胞重要构造相容性复合体Ⅰ类分子的表达[15],促进肿瘤微情况中干扰素(interferon,IFN)-γ等免疫调治因子产生,在增强抗肿瘤免疫反应中起着紧张作用[16,17]。有研究指出TIL团结12Gy可明显进步玄色素瘤患者客观缓解率[18]。然而,Goff等[19]研究体现TIL团结12Gy放疗并未明显进步客观反应率,且出现微小血管血栓性疾病等并发症。导致其不划一缘故起因大概与患者年岁、肿瘤病理范例、分期、肿瘤部位、敏感性及耐受情况等因素有关。现在放疗影响TIL治疗的具体机制仍不清晰,且疗效之外的不良反应不容忽视,仍需大量多中心随机临床试验证明。
1.3 TIL疗法团结免疫克制分子抗体治疗

步调性殒命受体1(programmed death-1,PD-1)是表达于T细胞外貌的一种紧张免疫克制分子[20,21],团结PD-1抗体治疗可增强TIL中T细胞活性。在PD-1抗体治疗希望的晚期玄色素瘤患者中,仍能从TIL治疗中获益[22,23]。别的,在Rosenberg团队[1,3]报道的转移性胆管癌和多发性晚期乳腺癌治愈案例中,TIL均团结应用了PD-1抗体治疗,表明团结PD-1抗体治疗在增强TIL治疗效果方面发挥了紧张作用。别的,Mullinax等[24]将细胞毒T淋巴细胞干系抗原4抗体伊匹单抗团结TIL治疗转移性玄色素瘤,观察到客观缓解为39%。现在TIL团结免疫克制分子抗体(PD-1、CTLA-4抗体)治疗实体肿瘤临床试验数据仍然有限,缺少多中心随机对照性研究,有待后续临床试验进一步开展。
1.4 新型TIL疗法

新型TIL疗法通过定向筛选TIL中存在的高反应性T细胞并举行扩增回输到患者体内,增强了抗肿瘤的靶向性、恒久性及安全性[25]。一项II期临床试验体现,66名晚期玄色素瘤患者接纳新型TIL(LN-144)治疗后观察到高达80%疾病控制率及36%的客观缓解率[26]。另一项II期临床试验体现,27例晚期宫颈癌患者接纳新型TIL(LN-145)治疗后观察到高达85%疾病控制率及44%客观缓解率,且未出现任何严峻的副作用[27]。相较于二线治疗4%~14%的化疗或免疫治疗应答率,LN-145在晚期宫颈癌治疗方面取得的疗效令人欣喜,现在该疗法已得到美国食品药品管理局用于晚期宫颈癌突破性治疗的认定。随着对TIL抗肿瘤作用的熟悉加深,新型TIL疗法也必将迎来新的突破。
综上,TIL已经从重要治疗晚期玄色素瘤的临床应用中扩展到恶性神经胶质瘤、胆管癌、乳腺癌、卵巢癌、宫颈癌、鼻咽癌、结直肠癌、肝癌、肾细胞癌和肺癌等临床试验阶段[28,29,30,31],并观察到肯定的疗效,同时袒暴露一些与治疗干系的不良反应,干系总结见表1
T细胞免疫治疗实体肿瘤的临床试验疗效分析


2
TCR-T疗法治疗实体肿瘤的临床试验疗效分析TCR是T细胞外貌表达的由α和β链异二聚体的肽链构成的受体,赋予了T细胞的抗原特异性。TCR-T疗法就是利用基因编辑将具有特异性辨认肿瘤抗原的TCR α和β链基因导入正常T细胞中,使其表达肿瘤特异性TCR杀伤肿瘤细胞[32]。常见的TCR靶点肿瘤抗原包罗肿瘤干系抗原(humor-associated antigen,TAA)和肿瘤特异性抗原(tumor specific antigen,TSA),针对差异靶点的TCR-T疗法疗效及安全性各异。因此,TCR靶点的选择尤为关键。现在,已开展了多个肿瘤抗原靶点的TCR-T临床试验,我们按几个常见靶点从临床疗效和不良反应方面临其重点叙述。
2.1 MART-1与gp100
T细胞辨认玄色素瘤抗原-1(melanoma-associated antigen recognized by T cells 1,MART-1)是第一个应用于TCR-T治疗的靶点抗原,险些仅表达于正常玄色素细胞和玄色素肿瘤细胞外貌。Morgan等[33]初次报道靶向MART-1的TCR-T治疗玄色素瘤观察到12%的客观缓解率,且MART-1特异性TCR-T细胞在体内存活长达一年之久。在Johnson等[34]研究中,将改进的MART-1(DMF5克隆)和玄色素瘤糖卵白100(glycoprotein 100,gp100)特异性TCR治疗转移性玄色素瘤患者,总体缓解率分别为30%和13%,但部门患者出现不良反应。MART-1与gp100作为较早应用于TCR-T疗法的肿瘤干系抗原,在转移性玄色素瘤患者中取得客观缓解率相对偏低,大概与其肿瘤特异性和亲和性较低有关。
2.2 NY-ESO-1
纽约食管鳞癌卵白(New York esophageal squamous cell carcinoma,NY-ESO-1)为癌症-睾丸抗原家属中的一员,在滑膜细胞肉瘤、玄色素瘤、乳腺癌、前线腺癌、卵巢癌等构造中高表达,而正常构造中仅在生殖细胞及构造中有表达[35]。Robbins等[4]开展的靶向NY-ESO-1的TCR-T临床试验体现,玄色素瘤及滑膜细胞肉瘤患者客观缓解率分别为45%和66.7%,且未发现与TCR-T细胞干系的不良反应。随后开展的II期临床试验体现,20例黑素瘤患者客观缓解率为55%,此中4例为完全缓解,且连续40个月以上;别的18例滑膜细胞肉瘤患者客观缓解率为61%,此中1例为完全缓解且连续20个月以上,同样未报道显着不良反应[5],表明NY-ESO-1可作为较为理想的TCR-T治疗肿瘤靶抗原。现在我国已有多个针对NY-ESO-1特异性TCR-T疗法临床试验项目得到我国国家食品药品监视管理总局答应,体现了我国在靶向NY-ESO-1的TCR-T治疗实体肿瘤方面也取得了较好的发展。
2.3 MAGE-A3
黑素瘤干系抗原(melanoma antigen,MAGE)-A3广泛表达于多种肿瘤构造及正凡人体胎盘和睾丸构造。针对MAGE-A3特异性TCR-T治疗的临床试验,Morgan等在8例患者中观察到63%的客观缓解率,此中1例滑膜肉瘤完全缓解,但出现了差异程度的神经体系侵害[36]。可见差异肿瘤范例应用同一种靶抗原产生的抗肿瘤作用疗效不一,大概与基因修饰后T细胞对表达靶抗原的肿瘤细胞辨认本领及亲和力差异有关。因此,探索针对各类晚期实体瘤特异性强、亲和力高的TCR靶抗原仍为当前TCR-T治疗面临的巨大挑衅。
2.4 新抗原
肿瘤新抗原(neoantigen)为体细胞基因突变产生并表达于细胞外貌的多肽,在正常构造细胞中不表达。作为TCR-T疗法的治疗靶点,具有特异性和安全性高等上风,为TCR-T疗法带来了新的思绪,未来以新抗原为根本的免疫治疗,制备高免疫原性肿瘤疫苗[37]、团结免疫克制剂(如PD-1抗体)及其他传统治疗方法大概成为实体肿瘤治疗的紧张发展方向。
现在开展的TCR-T临床试验中,涉及靶点有MART-1、gp100、MAGE-A3、NY-ESO-1、p53、癌胚抗原以及乙型肝炎病毒、人乳头瘤病毒等[38,39]。已有多个靶向肿瘤抗原的TCR-T临床试验观察到了较好的疗效,有关TCR-T细胞治疗临床实验疗效及不良反应总结见表2
T细胞免疫治疗实体肿瘤的临床试验疗效分析



3
T细胞免疫治疗不良反应T细胞免疫治疗固然在实体肿瘤治疗中取得令人鼓舞的结果,但同时也面临着临床安全性的题目。引起不良反应的因素有多种,起首,治疗前的淋巴扫除性化疗可导致肯定的血液学和非血液学毒性,如中性粒细胞镌汰,淋巴细胞镌汰等骨髓克制体现[13,40,41]。非血液学毒性包罗胃肠道反应、高胆红素血症以及神经毒性等[13,42,43]。其次,高剂量IL-2的易引起剂量和时间依靠的不良反应,可导致心脏、肝脏、肺、肾脏、甲状腺和脑等多个器官功能侵害[42,43,44]。别的,回输T细胞可辨认正常细胞导致自身免疫毒性,如白癜风或葡萄膜炎[13],以及分泌细胞因子等引起炎症反应等干系的不良反应[45,46]。
与TCR-T疗法密切干系的不良反应重要取决于TCR的靶抗原。一方面,正常细胞表达靶抗原可引起自身免疫毒性。如靶向MART-1、gp100和CEA[34,47,48]。另一方面,抗原结构相似也可引起交织反应。如靶向MAGE-A12与肌连卵白Titin表位,交织反应可引起神经毒性和心脏毒性[36,49]。
总体来说,TIL疗法毒副作用重要由淋巴细胞扫除性化疗和高剂量IL-2利用引起,相对TCR-T所致的脱靶毒性和细胞因子开释综合征发生率低。TCR-T疗法不良反应随着靶抗原及肿瘤范例的差异个体差异较大。现在针对T细胞免疫治疗不良反应的处理处罚重要是对症支持性治疗、减轻炎症反应、调治免疫等,尚无针对性处理处罚方案,仍需进一步深入研究不良反应产生气制及办理战略。


4
结语综上,T细胞免疫治疗已在多种实体肿瘤中开展临床试验,部门效果体现出较好的疗效。TIL团结低剂量IL-2明显镌汰了治疗的不良反应,团结淋巴细胞扫除性化疗、放疗及PD-1抗体治疗在进步临床疗效方面大概发挥着紧张作用。新型TIL疗法在抗肿瘤靶向性、连续性及安全性方面得到了较好的进步,以及肿瘤新抗原的筛选判定为晚期实体肿瘤患者免疫治疗提供了更加个性化的治疗方案。因此,筛选TIL高反应性T细胞、得到肿瘤驱动突变新抗原以及筛选肿瘤特异性TCR照旧当前研究的重点。随着肿瘤免疫逃逸机制不绝分析、干系分子生物学和免疫学技能不绝升级,T细胞治疗方案将向靶向性更强、安全性更好、可控性及通用性更高、本钱及耗时更低的方向不绝发展,在各种实体肿瘤治疗中显现更加理想的应用远景。
长处辩说 全部作者均声明不存在长处辩说


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