：肝细胞癌免疫治疗超进展的现状与应对策略.docx

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1、最新：肝细胞癌免疫治疗超进展的现状与应对策略摘要近年来，免疫检查点抑制剂(ICIs )在中晚期肝细胞癌治疗中大放异彩。随着ICIs应用日益广泛，部分病人接受ICIs治疗后出现了肿瘤超进展 (HPD),导致生存期显著缩短。HPD已然成为中晚期肝细胞癌病人ICIs 治疗不可忽视的问题。对于部分病人而言，HPD的临床结局是毁灭性的。 因此临床上需要结合HPD的易感因素及生物标记物评估病人能否从ICIs 治疗中获益，并且在治疗过程中实时监测治疗反应，加强对假性进展的鉴 别，将延长病人的总生存期(OS )作为最终目标。止矽卜，大多数HPD发 生时间在8周内，应探索最佳的疾病评估时间节点以早期识别HPD的

2、发 生。同时，由于HPD定义尚无统一标准且评估标准对基线前成像的依赖 性导致临床上病人的分层管理难以实现，建立通用且简便易行的标准对临 床前瞻性识别HPD病人至关重要。近年来，随着免疫检查点抑制剂(immune checkpoint inhibitors ,ICIs ) 在中晚期肝细胞癌(hepatocellular carcinoma , HCC )临床研究中取得 成功，ICIs已日趋成为中晚期HCC综合治疗中的优选方法口 1随着ICIs 在临床上广泛应用，部分HCC病人接受ICIs治疗后短期内出现了肿瘤超 进展(hyperprogressive disease , HPD ),导致其生存期

3、显著缩短2 1 HPD已然成为中晚期HCC免疫治疗中不可忽视的问题3 I故本文针对 HPD的定义、易感因素、发生机制以及应对策略等方面进行综述，以期能 1%、25%及210% )的ICIs治疗情况，结果表明PD-L1表达水平并不影 响治疗的预后。因此，未来还需开展前瞻性试验探索PD-L1表达水平与 HCC病人发生HPD的相关性。2.5 其他 有些学者还认为年龄 65岁53 1女性54 1转移灶 数目 2 55 1血清乳酸脱氢酶水平大于正常值的上限55 等也是HPD 的易感因素，但由于HCC中相关研究数据较少，还需进一步证实它们与 HPD的关系,才能制定适宜的评估标准。3肝癌HPD的发生机制目前

4、HPD的具体发生机制还未明确，但内部因素和外部因素都是导致 HPD的原因，内在因素指肿瘤细胞自身癌症基因或相关通路的过度激活或 突变，而外部因素则与肿瘤微环境(tumor microenvironment, TME ) 内免疫细胞的变化有关。1.1 MDM家族的扩增与表皮生长因子突变 MDM2/4扩增和表皮 生长因子(epidermal growth factor receptor, EFGR )突变与 HPD 有 显著相关性56 L p53是重要的抑癌基因,野生型p53可以诱导癌细胞 凋亡从而防止癌变,MDM2通过诱导p53降解抑制其抑癌功能,MDM2/4 扩增上调了这种抑制57 L止匕外，

5、MDM2/4扩增还与肿瘤的获得性耐药 相关58 I在HCC中，MDM2可通过与含杆状病毒IAP重复序列蛋白 5 ( baculoviral IAP repeat-containing protein 5 , BIRC5 )直接或间接 作用上调BIRC5表达，进而调控错配修复(mismatch repair, MMR )基因，导致HCC对ICIs治疗的敏感度下降59 LEFGR突变会引起肿瘤免疫抑制微环境、肿瘤突变负荷以及PD-L1表 达水平等一系列改变，最终导致病人出现较差的免疫治疗反应60 1，另 有研究发现EFGR突变免疫缺陷小鼠移植瘤拥有与HPD病人相似的组织 学特征，并且有较高的TGR

6、和肿瘤扩散61 I尽管这些基因在HCC中 还未被证实与HPD发生密切相关但也提示在ICIs治疗前进行基因检测， 可能有助于预测HPD发生的可能性。1.2 调节性T细胞和肿瘤相关巨噬细胞 ICIs治疗后TME的变化可 能与HPD有关，这其中免疫细胞亚群如调节性T细胞(regulatory T cells ,Tregs )和肿瘤相关巨噬细胞(tumor-associated macrophages , TAMs )的异常改变扮演了重要角色62 LTregs是CD4+T细胞的一个免疫抑制亚群，是维持自身免疫耐 受的重要环节。一项对胃癌组织的分析提示，HPD病人在治疗后肿瘤组织 中的Tregs显著增加

7、63 ,单细胞RNA测序分析显示在HPD组中观察 到耗竭的CD4+ T细胞和富集的Treg 64 L止匕外,Wakiyama等65 构建了一个由Treg主导TME的动物模型来探索HPD与Treg的关系，结 果提示TME中Treg与CD8+ T细胞的比例失衡可能是HPD的原因。研究表明ICIs可诱导TAMs的M2样分化 从而塑造免疫抑制微 环境61 1在一项非小细胞肺癌回顾性研究中，病理学分析显示所有HPD 病例及小鼠的肿瘤结节中均观察到TAMs的富集并表达一种特异的免疫表 型(CD163+CD33 + PD-L1+ ),这可能是HPD的一个独特特征61 4 肝癌HPD的应对策略4.1 病人筛选

8、临床上对于HPD的防治，需要明确预防大于治疗的宗旨，预防HPD的首要步骤是通过识别已知的危险因素来筛选纳入治疗 的病人66 1研究表明既往放疗史可能是HPD的危险因素7 L在临床 指标方面，基线NLR水平，血红蛋白水平,PVTT和肝功能Child-Pugh 评分能够为预测HPD提供参考，尽管对NLR的截断值尚未达成共识，但 较高的基线NLR无疑是HPD的危险因氯2,10 I而联合血红蛋白水平、 PVTT和肝功能Child-Pugh评分的HPD预测模型AUC高达0.931 9 1 此外，完善基因检测也对HPD的预防有着重要意义56 14.2 治疗过程中HPD的评估 对于接受ICIs治疗的病人，对

9、于治疗 的评估和实时监测是至关重要的。Champiat等67 指出TGR和TGK 是判定HPD的重要指标，并建议将首次评估时间提前，这将有助于早期 识别HPD。除了影像学评估，密切监测病人生命体征及临床指标如NLR 的动态增长也可预测HPD的发生11 1同时，建议临床医生在条件允许 时对可疑病变进行病理活检,这可能有助于对HPD机制的理解并指导治 疗方案的制定67 ；4.3 HPD病人的处理对于出现HPD的病人，首要措施是立即停止ICIs治疗，更换为其他系统治疗方法，如化疗、靶向治疗和最佳支持治 疗等，以减少对病人的伤害13 L我国最新的多学科专家共识指出18 : 既往应用ICIs联合酪氨酸激

10、酶抑制剂(tyrosine kinase inhibitors ,TKI) 方案者可考虑选择系统化疗，既往应用ICIs联合抗血管生成药物者可考 虑选择兼有抗增殖作用的仑伐替尼。同时应密切监测病人的各种生命体征、 指标，建议缩短影像学评估周期，以便针对新发情况调整治疗方案。5 结语ICIs在中晚期HCC治疗中有着良好的应用前景和疗效，但对于部分病人 而言，HPD的临床结局是毁灭性的。因此，临床上需要结合HPD的易感 因素及生物标记物评估病人能否从ICIs治疗中获益，并且在治疗过程中实 时监测治疗反应，加强对假性进展的鉴别，将延长病人的OS作为最终目 标。此外，大多数HPD发生时间在8周内，应探索

11、最佳的疾病评估时间 节点以早期识别HPD的发生。同时，由于HPD定义尚无统一标准且评估 标准对基线前成像的依赖性导致临床上病人的分层管理难以实现，建立通 用且简便易行的标准对临床前瞻性识别HPD病人至关重要。未来需要开 展更多的研究来统一 HPD的定义，明确HPD的机制，探索更为敏感和特 异的生物标记物以及开发新生代检测技术，能更好地预防HPD的发生并 指导HPD的治疗。参考文献1 中国医师协会肝癌专业委员会.肝细胞癌免疫治疗中国专家共识(2021 版)J .中华医学杂志,2021 ,101 (48 ): 3921 -3931.2 Maesaka K ,Sakamori R ,Yamada R

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29、 2021 z 21 ( 1 ): 401.30 Watanabe Y , Ogawa M , Tamura Y , et a LA case of 为HPD的早期识别和治疗提供参考。1 HPD与假性进展1.1 HPD自从2016年首次在非小细胞肺癌中报道ICIs治疗相关HPD以来，学者们对HPD的定义尚未达成共识4-5 L目前HCC相关HPD文献中的评价标准皆基于实体瘤疗效评价标准(response evaluation criteria in solid tumors , RECIST ) 1.1 6 ,主要使用肿瘤 生长速率(tumor growth rate , TGR ),即ICIs

30、治疗期间每月靶病灶体 积之和的对数校正变化肿瘤生长动力学(tumor growth kinetics ,TGK ) 即每月靶病灶最长直径之和的变化和治疗失败时间(time to treatment failure , TTF )等指标来定义HPD ,正因为其评价标准和样本量各异，目前HCC的HPD发生率为8.00%14.49% 2, 7-11 (表1%Kim等10比较了多个HPD评价标准 发现基于TGR和TGK的标准评估HPD 的一致性较基于TTF的标准更高，这提示对于HCC病人而言，采用基于 肿瘤生长指标构建的标准来评价HPD可能更为合适。然而，目前仍缺乏统一的HPD评价标准，这将阻碍临床上

31、前瞻 性识别HPD的发生,不利于HCC病人的后续治疗。因此，还需更大样本 量的前瞻性试验来进一步探索更加适用的HPD统一评价标准。1.2 假性进展目前临床上关于假性进展(pseudoprogression )的定义尚缺乏统一标准。一般认为，ICIs治疗初期出现肿瘤体积增大或新 pseudoprogression in hepatocellular carcinoma treated with atezolizumab plus bevacizumab J J Investig Med High Impact Case Rep , 2021 , 9 : 23247096211058489.31

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