探讨肝癌肝移植术后复发患者安全应用程序性死亡受体-1(PD-1)单克隆抗体(以下简称单抗)的治疗策略。

本研究纳入4例一线靶向药物治疗后肿瘤仍进展的肝癌肝移植术后复发患者，进行移植肝穿刺免疫组织化学检测程序性死亡配体-1(PD-L1)表达均为阴性。患者接受PD-1抑制剂卡瑞利珠单抗治疗，每3周1次，200 mg/次，并选择合适的靶向药物联合治疗，同时将免疫抑制方案调整为哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂联合霉酚酸类药物。随访期间综合分析患者肝功能、甲胎蛋白(AFP)以及胸腹部影像学检查等变化情况，评估PD-1单抗的有效性与安全性。

截至2021年2月，4例患者中存活2例，分别随访17.3和15.3个月，期间均接受PD-1单抗治疗6次，有乏力、腹泻和高血压等不良反应，经对症治疗后均好转，仍处于持续随访中。病例1因肺部转移瘤压迫气管和支气管引起严重肺部感染，于PD-1单抗治疗后6.3个月死亡(期间共接受PD-1单抗治疗6次)；病例4因肺部转移瘤压迫支气管引起肺炎、肺不张和双侧胸水，于PD-1单抗治疗后10.9个月死亡(期间共接受PD-1单抗治疗3次)。4例患者使用PD-1单抗治疗后，AST水平均处于相对稳定状态，偶有波动也可通过护肝治疗较快恢复正常；血清白蛋白波动于30~45 g/L；总胆红素处于正常水平，均未发生黄疸；3例患者AFP均有不同程度下降。随访期间患者均未发生明显排斥反应。使用PD-1单抗治疗后，改良的实体肿瘤疗效评价标准评估3例患者为疾病稳定，中位无进展生存期为141 d；另1例患者评估为部分缓解，中位无进展生存期为180 d。

移植肝组织PD-L1表达阴性的肝癌肝移植术后复发患者，在mTOR抑制剂联合霉酚酸类药物维持有效免疫抑制状态下使用PD-1单抗是相对安全的，但其有效性与长期临床获益仍需进一步观察。

To investigate the safe application of programmed death-1 (PD-1) monoclonal antibody in patients with recurrent liver cancer after liver transplantation.

Four patients with recurrent hepatocellular carcinoma after liver transplantation who still progressed after first-line targeted drug therapy were included in this study, and programmed death ligand-1 (PD-L1) expression was negative by immunohistochemistry of liver allograft puncture. Patients were treated with the PD-1 inhibitor Camrelizumab, 200 mg every 3 weeks, and the appropriate targeted drug combination was selected, while the immunosuppressive regimen was adjusted to mammalian target of rapamycin (mTOR) inhibitors in combination with mycophenolate mofetil. Blood routine, liver and kidney function, alpha-fetoprotein (AFP) and thoracic and abdominal imaging examinations were measured during follow-up, and changes in liver function and tumor parameters during follow-up were comprehensively analyzed to evaluate the efficacy and safety of PD-1 monoclonal antibody.

By February 2021, 2 of the 4 patients survived and were followed up for 17.3 and 15.3 months, respectively, during which they all received PD-1 monoclonal antibody for 6 times, with adverse reactions such as fatigue, diarrhea and hypertension, which were improved after symptomatic treatment and are still under continuous follow-up. In Case 1, the patient died 6.3 months after PD-1 monoclonal antibody treatment due to severe lung infection caused by compression of trachea and bronchus by pulmonary metastases (a total of 6 times of PD-1 monoclonal antibody treatment were performed during this period); in Case 4, the patient died 10.9 months after PD-1 monoclonal antibody treatment due to pneumonia, atelectasis and pleural effusion caused by compression of bronchus by pulmonary metastases (a total of 3 times of PD-1 monoclonal antibody treatment were performed during this period). Four patients were treated with PD-1 monoclonal antibody. However, AST levels were in a relatively stable state, and occasional fluctuations can also be quickly restored to normal by liver protection therapy; serum albumin fluctuated between 30 and 45 g/L; total bilirubin was in a normal level, and no jaundice occurred; AFP decreased to varying degrees in 3 patients. None of the patients developed significant rejection during the follow-up period. After treatment with PD-1 monoclonal antibody, 3 patients had stable disease assessed by the modified Response Evaluation Criteria in Solid Tumors, with a progression-free survival of 141 days; the other patient had a partial response assessed, with a progression-free survival of 180 days.

PD-1 monoclonal antibody is relatively safe in patients with PD-L1-negative recurrent hepatocellular carcinoma after liver transplantation under the effective immunosuppressive state of mTOR inhibitor combined with mycophenolate mofetil, but its effectiveness and long-term clinical benefit still need further observation.