Department of Medical Oncology, Dana Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Oncologist. 2020 Jun;25(6):505-514. doi: 10.1634/theoncologist.2019-0659. Epub 2020 Feb 11.
Limited data exist on safety and efficacy of immune checkpoint inhibitors (ICIs) among organ transplant recipients. The objective of this study was to report a case series of two patients with renal transplant who received treatment with an ICI and to conduct a pooled analysis of published cases to describe the safety and efficacy of ICIs in organ transplant patients. A systematic search in the Google Scholar and PubMed databases was carried out to include all the published cases of organ transplant patients who received treatment with ICIs including programmed cell death protein 1 (PD-1), programmed death-ligand 1, or cytotoxic lymphocyte antigen-4 inhibitors since their inscription to January 31, 2019. In the present series of two cases with renal allografts who received pembrolizumab, one patient with squamous cell carcinoma of the skin experienced complete response (CR), whereas another patient with melanoma had a mixed response. Both patients experienced allograft rejection, but graft was salvaged. The pooled analysis of 64 patients published in literature showed that overall allograft rejection rate is 41% in organ transplant recipients following ICI therapy. The graft rejection rate was 44% (17/39) for renal, 39% (7/19) for liver, and 20% (1/5) for cardiac allografts. The highest risk was seen among patients who were treated with PD-1 inhibitors, 20/42 (48%)-13/24 (54%) on nivolumab and 7/18 (39%) on pembrolizumab. The risk was lowest with ipilimumab, 23% (3/13). The overall response rate (CR + partial response [PR]) was 20% with ipilimumab, 26% with nivolumab, and 53% with pembrolizumab, whereas disease control rate (CR + PR + stable disease) was 35% with ipilimumab, 37% with nivolumab, and 53% with pembrolizumab. None of the variables including age, gender, type of cancer, type of allograft, type of immunosuppression, time since transplantation to initiation of ICI, and prior history of rejection were significantly associated with the transplant rejection on univariate analysis. The efficacy of ICI among patients with organ transplant appears promising, warranting testing in prospective clinical trials. The risk of rejection and allograft loss is considerable; therefore, the risk and alternative form of therapies should be thoroughly discussed with the transplant patients prior to initiating ICI therapy. IMPLICATIONS FOR PRACTICE: Transplant recipients are at higher risk of developing cancers. Although immune checkpoint inhibitors have been shown to improve the outcome in more than one cancer type, transplant recipients were excluded from these trials. Most of the data on the safety and efficacy of immune checkpoint inhibitors in transplant patients are based upon case series and case reports. The pooled data from these reports suggest that anti-programmed death-ligand 1 inhibitors have reasonable safety and efficacy among organ transplant patients, which warrants testing in clinical trials.
关于免疫检查点抑制剂（ICIs）在器官移植受者中的安全性和疗效的数据有限。本研究的目的是报告两例接受 ICI 治疗的肾移植患者的病例系列，并对已发表的病例进行汇总分析，以描述 ICI 在器官移植受者中的安全性和疗效。在 Google Scholar 和 PubMed 数据库中进行了系统检索，以纳入自 2019 年 1 月 31 日起接受 ICI 治疗的包括程序性细胞死亡蛋白 1（PD-1）、程序性死亡配体 1 或细胞毒性淋巴细胞抗原-4 抑制剂在内的所有已发表的器官移植患者病例。在本系列的两例接受 pembrolizumab 治疗的肾同种异体移植患者中，一例患有皮肤鳞状细胞癌的患者经历了完全缓解（CR），而另一例患有黑色素瘤的患者则出现了混合反应。两名患者均经历了同种异体移植物排斥反应，但移植物得以挽救。文献中发表的 64 例患者的汇总分析显示，ICI 治疗后器官移植受者的同种异体移植物排斥率总体为 41%。肾移植患者的排斥率为 44%（17/39），肝移植患者为 39%（7/19），心脏移植患者为 20%（1/5）。接受 PD-1 抑制剂治疗的患者风险最高，20/42（48%）-13/24（54%）接受 nivolumab 治疗，7/18（39%）接受 pembrolizumab 治疗。接受 ipilimumab 治疗的患者风险最低，为 23%（3/13）。接受 ipilimumab 治疗的总体缓解率（CR+部分缓解[PR]）为 20%，nivolumab 为 26%，pembrolizumab 为 53%，而疾病控制率（CR+PR+稳定疾病）为 ipilimumab 为 35%，nivolumab 为 37%，pembrolizumab 为 53%。单变量分析显示，年龄、性别、癌症类型、同种异体移植物类型、免疫抑制类型、ICI 开始至移植后时间以及既往排斥反应史等变量均与移植排斥反应无显著相关性。ICI 治疗器官移植患者的疗效似乎很有前景，值得在前瞻性临床试验中进行测试。排斥反应和移植物丢失的风险相当大；因此，在开始 ICI 治疗之前，应与移植患者充分讨论风险和替代治疗方案。
移植受者发生癌症的风险较高。尽管免疫检查点抑制剂已被证明可改善多种癌症类型的预后，但这些试验均排除了移植受者。关于移植患者中免疫检查点抑制剂的安全性和疗效的数据主要基于病例系列和病例报告。这些报告的汇总数据表明，抗程序性死亡配体 1 抑制剂在器官移植患者中具有合理的安全性和疗效，值得在临床试验中进行测试。
