：肝细胞癌免疫治疗超进展的现状与应对策略.docx

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，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 ,et al.Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy J JHepatol Res , 2022 ,52 ( 3 ): 298-307.3 陈亚进.肝癌转化治疗现状与思考J .中国实用外科杂志，2021,41(3):253-256 , 261.4 Lahmar J , Facchinetti F , Koscielny S , et al. Effect of tumor growth rate(TGR)on response patterns of checkpoint inhibitors in non-small cell lung cancer(NSCLC) J J Clin Oncol , 2016 , 34(suppl15):9034.5 Adashek JJ , Subbiah IM , Matos I, et al.Hyperprogression and immunotherapy: fact, fiction, or alternative fact? J .Trends Cancer, 2020 ,6 ( 3 ): 181-191.6 宋天强，刘雅月.原发性肝癌转化治疗及其维持治疗策略J .中国实用外科杂志，2021,41(3):269-272.7 Wong DJ , Lee J , Choo SP , et al.Hyperprogressive disease in hepatocellular carcinoma with immune checkpoint inhibitor use: a case series J .Immunotherapy , 2019 z 11 ( 3 ): 167-175.8 Scheiner B , Kirstein MM , Hucke F , et al.Programmed cell death protein-1 (PD-l)-targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicentre real-world cohort J .Aliment Pharmacol Ther, 2019,49 ( 10 ): 1323-1333.9 Zhang L ,Wu L ,Chen Q zet al.Predicting hyperprogressive disease in patients with advanced hepatocellular carcinoma treated with anti-programmed cell death 1 therapy J .ECIinicalMedicine , 2020 , 31 : 100673.10 Kim CG , Kim C , Yoon SE , et al.Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma J J Hepatol , 2021 , 74 ( 2 ): 350-359.11 Choi WM , Kim JY , Choi J , et aLKinetics of the neutrophil-lymphocyte ratio during PD-1 inhibition as a prognostic factor in advanced hepatocellular carcinoma J .Liver Int, 2021 , 41 ( 9 ): 2189-2199.12 Chiou VL , Burotto M.Pseudoprogression and immune-related response in solid tumors J J Clin Oncol , 2015 , 33 ( 31 ): 3541-3543.13 Billan S , Kaidar-Person O , Gil Z.Treatment after progression in the era of immunotherapy! J .Lancet Oncol ,2020 , 21 ( 10 ): e463-e476.14 Wolchok JD , Hoos A , O'Day S , et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria J .Clin Cancer Res , 2009 , 15 (23 ): 7412-7420.15 Seymour L , Bogaerts J , Perrone A , et alJRECIST:guidelines for response criteria for use in trials testing immunotherapeutics J .Lancet Oncol z 2017,18(3): e143-e152.16 Lee DH , Hwang S , Koh YH , et al.Outcome of initial progression during nivolumab treatment for hepatocellular carcinoma: should we use iRECIST? J .Front Med ,2021 ,8 :771887.17 Lewis S , Cedillo MA , Lee KM , et al.Comparative assessment of standard and immune response criteria for evaluation of response to PD-1 monotherapy in unresectable HCCJ .Abdom Radiol (NY) , 2022,47 ( 3 ): 969-980.18国际肝胆胰协会中国分会，中华医学会外科学分会肝脏外科学 组，中国临床肿瘤学会（CSCO ）肝癌专家委员会.基于免疫节点抑制剂的肝细胞癌免疫联合治疗多学科中国专家共识（2021版）J .中华肝脏病杂志，2021 , 29 ( 7 ): 636-647.19 Borcoman E , Nandikolla A , Long G , et al. Patterns of response and progression to immunotherapy J . Am Soc Clin Oncol Educ Book z 2018 z 38:169-178.20 Kawamura Y ,Kobayashi M ,Shindoh J ,et al.Pretreatment positron emission tomography with 18f-fluorodeoxyglucose may be a useful new predictor of early progressive disease following atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma J .Oncology z 2022,100 ( 6 ): 320-330.21 Mamdani H , Wu H , O'Neil BH , et al.Excellent response to Anti-PD-1 therapy in a patient with hepatocellular carcinoma: case report and review of literature! J .Discov Med ,2017 ,23( 128 ): 331-336.22 Wang Q , Gao J , Wu X.Pseudoprogression and hyperprogression after checkpoint blockade J .Int Immunopharmacol , 2018 , 58 : 125-135.23 Park HJ ,Kim KW zWon SE ,et al.Definition, incidence, and challenges for assessment of hyperprogressive disease during cancer treatment with immune checkpoint inhibitors: a systematic review and meta-analysis J JAMA Network Open ,2021 ,4( 3 ): e211136.24 Ma Y z Wang Q , Dong Q , et al.How to differentiate pseudoprogression from true progression in cancer patients treated with immunotherapy J .Am J Cancer Res , 2019 ,9(8): 1546-1553.25 Tabei T Jsuura Y ,Kobayashi K.Pseudoprogression: A case of metastatic renal clear cell carcinoma treated with nivolumabJ .Pathol Int, 2018 z 68 ( 11 ): 627-629.26 Di Giacomo AM , Danielli R , Guidoboni M , et al.Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases J .Cancer Immunol Immunother, 2009 , 58 ( 8 ): 1297-1306.27 Tanizaki J zHayashi H Kimura M ,et al.Report of two cases of pseudoprogression in patients with non-small cell lung cancer treated with nivolumab-including histological analysis of one case after tumor regression J .Lung Cancer z 2016 z 102 : 44-48.28 Wang W , Wei C.Advances in the early diagnosis of hepatocellular carcinoma J .Genes Dis , 2020 z 7 ( 3 ): 308-319.29 Feng H ; Li B , Li Z , et al.PIVKA-II serves as a potential biomarker that complements AFP for the diagnosis of hepatocellular carcinoma J .BMC Cancer z 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 Shigefuku R , Yosh汰awa K , Tsukimoto M , et al.Hepatocellular carcinoma pseudoprogression involving the main portal vein, right ventricular invasion, and exacerbation of lung metastases in a patient on atezolizumab plus bevacizumabJ .Intern Med J , 2023 , 62 ( 4 ): 539-543.32 Bettegowda C , Sausen Ml , Leary RJ , et al.Detection of circulating tumor DNA in early- and late-stage human malignancies J .Sci Transl Med , 2014,6 ( 224): 224ra24.33 Riva F zBidard FC ,Houy A ,et aLPatient-specific circulating tumor DNA detection during neoadjuvant chemotherapy in triple-negative breast cancer J .CIin Chem ,2017 ,63( 3 ) :691 -699.34 Hsu CH , Lu S z Abbas A , et aL Longitudinal and personalized detection of circulating tumor DNA(ctDNA)for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma(HCC) J . J Clin Oncol ,2020, 38(suppl 15):3531.35 Howell J , Atkinson SR , Pinato DJ , et al.Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma J .Eur J Cancer, 2019 , 116: 56-66.36 Ao H , Xin Z z Jian Z.Liquid biopsy to identify biomarkers for immunotherapy in hepatocellular carcinoma J .Biomark Res , 2021 , 9 ( 1 ): 91.37 Sachpekidis C , Kopp-Schneider A , Hassel JC , et al.Assessment of early metabolic progression in melanoma patients under immunotherapy: an 18F-FDG PET/CT study J JEJNMMI Res , 2021 , 11 ( 1 ): 89.38 Margetts J , Ogle LF , Chan SL , et al.Neutrophils: driving progression and poor prognosis in hepatocellular carcinoma? J .Br J Cancer, 2018 ,118 ( 2 ): 248-257.39 Muhammed A z Fulgenzi CAM , Dharmapuri S , et al.The systemic inflammatory response identifies patients with adverse clinical outcome from immunotherapy in hepatocellular carcinomaJ .Cancers , 2021 z 14 ( 1 ): 186.40 Wong L z Bozhilov K , Hernandez B , et al.Underlying liver disease and advanced stage liver cancer are associated with elevated neutrophil-lymphocyte ratio J .CIin Mol Hepatol z2019 , 25 ( 3 ): 305-316.41 Kim J , Kim T , Jang TW , et al.Clinical outcomes of hyperprogression based on volumetry in non-small cell lung cancer after immune checkpoint inhibitor treatment J .Thorac Cancer, 2022 ,13 ( 15 ): 2170-2179.42 Floridi C , Pesapane F , Angileri SA , et al.Yttrium-90 radioembolization treatment for unresectable hepatocellular carcinoma: a single-centre prognostic factors analysis J .Med Oncol , 2017 , 34 ( 10 ): 174.43 Lu J ,Zhang XP ,Zhong BY zet al.Management of patients with hepatocellular carcinoma and portal vein tumour thrombosis: comparing east and west J .Lancet Gastroenterol Hepatol z2019 , 4 ( 9 ): 721-730.44 Saada-Bouzid E , Defaucheux C , Karabajakian A , et al.Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma J .Ann Oncol z 2017 z 28 ( 7 ): 1605-1611.45 Darragh LB ,Oweida AJ ,Karam SD.Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways within the tumor microenvironment! J .Front Immunol , 2019,9 : 3154.46 Kim JY , Lee KH , Kang J , et al.Hyperprogressive disease during anti-PD-1 (PDCD1) / PD-L1 (CD274) therapy: A systematic review and meta-analysis J .Cancers , 2019 ,11 ( 11 ): 1699.47 Hagi T z Kurokawa Y , Kawabata R , et al.Multicentre biomarker cohort study on the efficacy of nivolumab treatment for gastric cancer J .Br J Cancer, 2020 , 123 ( 6 ): 965-972.48 Petrioli R z Mazzei MA , Giorgi S , et aLHyperprogressive disease in advanced cancer patients treated with nivolumab: a case series study J .Anticancer Drugs , 2020 ,31 ( 2 ): 190-195.49 Zhu AX , Finn RS , Edeline J , et al.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial J .Lancet Oncol , 2018 z 19 ( 7 ): 940-952.50 Morita M , Nishida N , Sakai K , et al.Immunological microenvironment predicts the survival of the patients with hepatocellular carcinoma treated with anti-PD-1 antibody J .Liver Cancer, 2021 , 10 (4): 380-393.51 El-Khoueiry AB , Sangro B , Yau T , et al.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial J lancet, 2017 , 389 ( 10088 ): 2492-2502.52 Lee MS , Ryoo BY , Hsu CH , et al.Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (G030140): an open-label, multicentre, phase 1b study J .Lancet Oncol , 2020 , 21 ( 6 ): 808-820.53 Champiat S , Dercle L , Amman S , et al.Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1 J .CIin Cancer Res ,2017 ,23( 8 ):1920-1928.54 Kanjanapan Y , Day D , Wang L , et al.Hyperprogressive disease in early-phase immunotherapy trials: Clinical predictors and association with immune-related toxicities J .Cancer, 2019 , 125 ( 8 ): 1341-1349.55 Kim CG , Kim KH , Pyo KH z et al.Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer J .Ann Oncol , 2019 , 30 ( 7 ): 1104-1113.56