The Safety and Efficacy of Checkpoint Inhibitors in Transplant Recipients: A Case Series and Systematic Review of Literature

Abstract

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.

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors

“…In a recently published review of the literature, the incidence of acute rejection in LT recipients treated with ICIs was reported to be 39%. 58 PDL-1 expression in the allograft seems to be correlated with rejection, 59 , 60 although a panel of validated risk factors is lacking. However, safe employment of immunotherapy after LT has also been described.…”

A Pilot Study of Checkpoint Inhibitors in Solid Organ Transplant Recipients with Metastatic Cutaneous Squamous Cell Carcinoma

“…Oncologists are increasingly using immune checkpoint inhibitors (ICIs) such as antibodies targeting programmed cell death 1 (PD-1) in numerous advanced solid organ malignancies. However, the safety and efficacy of anti-PD-1 therapy in solid organ transplant (SOT) recipients are largely unknown, as these patients are routinely excluded from clinical trials because of their risk for severe and irreversible allograft rejection [1][2][3].…”

Immune checkpoint inhibitor therapy-associated graft intolerance syndrome in a failed kidney transplant recipient

“…ICPIs are well‐tolerated but their immune‐mediated adverse reactions are increasingly being recognized. Several case series have suggested an association between acute allograft rejection and ICPI therapy among SOT recipients 3–6 . In the setting of a functioning allograft, this scenario poses a tough challenge to the care team and the patient.…”

“…Of those who developed rejection, 83% progressed to allograft failure which was fivefold higher than the rate of progression of those who did not develop rejection 3 . No significant association has been found between the occurrence of rejection and factors like the class of ICPI used, immunosuppression regimen, steroid dose, history of rejection, and time from transplant to ICPI initiation 3–5 …”