Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Bristol Myers Squibb.

中文翻译：

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肾移植受者的免疫检查点抑制剂：一项多中心、单臂、1 期研究

背景

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之前会停止或减少免疫抑制治疗，大约 40% 的此类患者会出现同种异体移植排斥。孤立的免疫抑制降低可能与器官排斥有关。难以确定免疫抑制操作、免疫检查点抑制或两者是否诱导器官排斥。本研究的目的是检查当基线免疫抑制保持不变时，暴露于免疫检查点抑制剂的同种异体移植排斥风险。

方法

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。18 岁或以上患有无法治愈的局部晚期癌症或明确的转移性实体瘤的肾移植受者，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，以及东部合作组织肿瘤学组状态为 0-2。患者接受标准剂量的纳武利尤单抗（每 14 天静脉注射 3 mg/kg，共 5 个周期，然后每 28 天 480 mg，最长 2 年）。主要终点是具有不可挽回的同种异体移植物排斥且无肿瘤反应证据的患者比例。在改良意向治疗人群中进行了主要结果分析和安全性分析。

发现

2017 年 5 月 31 日至 2021 年 8 月 6 日期间，筛选并入组了 22 名患有各种实体瘤的肾移植受者，其中 4 人选择不继续研究，其中 1 人出现意外疾病进展。17 名患者（6 名 [35%] 女性和 11 名 [65%] 男性；中位年龄 67 岁 [IQR 59-71]）被分配接受纳武单抗治疗并被纳入分析。由于在 COVID-19 健康限制期间进行临床试验持续存在困难，该试验随后停止。患者接受中位输注 3 次（IQR 2-10），中位随访时间为 28 个月（IQR 16-34）。在没有肿瘤反应证据的情况下，没有患者出现不可挽回的同种异体移植排斥。没有与治疗相关的死亡或与治疗相关的严重不良事件。

解释

在肾移植受者使用免疫检查点抑制剂治疗前维持基线免疫抑制可能不会影响预期疗效，并可能降低免疫检查点抑制剂介导的同种异体移植物排斥风险。

资金

百时美施贵宝。