Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, SA, Australia; Department of Health Sciences, University of South Australia, Adelaide, SA, Australia.
Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
Lancet Oncol. 2022 Aug;23(8):1078-1086. doi: 10.1016/S1470-2045(22)00368-0. Epub 2022 Jul 6.
Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged.
We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0-2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed.
Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59-71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2-10) and median follow-up was 28 months (IQR 16-34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients.
Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors.
Bristol Myers Squibb.
大多数患有癌症的肾移植受者在开始使用免疫检查点抑制剂治疗前会停止或减少免疫抑制治疗，约 40%的此类患者会发生移植物排斥反应。单独减少免疫抑制可能与器官排斥有关。免疫抑制的操纵、免疫检查点抑制或两者都诱导器官排斥反应是难以确定的。本研究旨在检查在基线免疫抑制不变的情况下，免疫检查点抑制剂暴露时发生移植物排斥的风险。
我们在澳大利亚的三家医院进行了一项多中心、单臂、1 期研究。年龄在 18 岁及以上、患有无法治愈的局部晚期癌症或明确转移性实体瘤的肾移植受者符合条件，如果他们的肌酐浓度低于 180 mmol/L，没有或低浓度的供体特异性 HLA 抗体，以及东部合作肿瘤组状态为 0-2。患者接受标准剂量的纳武单抗（每 14 天静脉注射 3 mg/kg，共 5 个周期，然后每 28 天静脉注射 480 mg，最长 2 年）。主要终点是不可逆转的移植物排斥和无肿瘤反应证据的患者比例。主要结局分析和安全性分析在改良意向治疗人群中进行。该试验在澳大利亚和新西兰临床试验注册处进行，注册号为 ANZCTR12617000741381，现已完成。
2017 年 5 月 31 日至 2021 年 8 月 6 日，共有 22 名患有各种实体瘤的肾移植受者接受了筛查和入组，其中 4 名受者选择不参加研究，1 名受者出现意外疾病进展。17 名患者（6 名[35%]女性和 11 名[65%]男性；中位年龄 67 岁[IQR 59-71]）接受纳武单抗治疗并纳入分析。由于在 COVID-19 健康限制期间进行临床试验的困难，试验随后停止。患者接受了中位 3 次输注（IQR 2-10），中位随访时间为 28 个月（IQR 16-34）。没有患者发生无肿瘤反应的不可逆转的移植物排斥。没有与治疗相关的死亡或与治疗相关的严重不良事件。最常见的 3 级或 4 级不良事件是 4 名（24%）患者的淋巴细胞计数下降、4 名（24%）患者的发热或感染、3 名（18%）患者的血红蛋白下降和 3 名（18%）患者的肌酐升高。
在肾移植受者开始使用免疫检查点抑制剂之前维持基线免疫抑制可能不会影响预期的疗效，并可能降低免疫检查点抑制剂介导的移植物排斥反应的风险。
百时美施贵宝公司。
