Utility of Serial Donor-derived Cell-free DNA Measurements for Detecting Allograft Rejection in a Kidney Transplant Recipient After PD-1 Checkpoint Inhibitor Administration

Abstract

Background. Donor-derived cell-free DNA (dd-cfDNA) is a useful biomarker of rejection that originates from allograft cells undergoing injury. Plasma levels <1% in kidney transplant recipients have a high negative predictive value for active allograft rejection. The utility of this biomarker in kidney transplant recipients receiving immune checkpoint inhibitor therapy is unknown. Methods. We describe a case in which serial dd-cfDNA monitoring facilitated the use of immune checkpoint inhibitor therapy, which is known to be associated with high rates of rejection, in a kidney transplant recipient with metastatic cancer. Results. A 72-y-old man with end-stage kidney disease secondary to autosomal dominant polycystic kidney disease underwent living unrelated kidney transplant in December 2010. His immunosuppression regimen included tacrolimus, mycophenolate, and prednisone. In July 2017, he presented with metastatic cutaneous squamous cell carcinoma. After his disease progressed through radiation therapy and cetuximab, he received pembrolizumab (antiprogrammed cell death protein 1). His dd-cfDNA level was undetectable at baseline, then increased during treatment but remained <1%. This trend, despite fluctuations in serum creatinine levels during therapy, allowed for continuation of pembrolizumab and successful treatment of his metastatic cancer without clinically evident allograft rejection. After discontinuation of pembrolizumab, dd-cfDNA levels fell below the level of detection. Genetic analysis of the cutaneous squamous cell carcinoma demonstrated a genetic profile distinct from the dd-cfDNA, indicating that tumor lysis did not impact increases in dd-cfDNA. Conclusions. Serial dd-cfDNA measurements may provide a useful, noninvasive biomarker for detecting allograft injury that may facilitate the use of immunomodulatory therapies in organ transplant recipients with cancer.

Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers

“…Because dd-cfDNA levels were exploratory, the results were not used as a basis for clinical decision making. 30,47 On the basis of the results described above, we designed a clinical trial (ClinicalTrials.gov identifier: NCT05896839) testing the safety and efficacy of an mTOR inhibitor-based regimen (sirolimus 1 PRED) plus NIVO 1 IPI in KTR with advanced MEL, BCC, CSCC, or MCC. We will use real-time changes in dd-cfDNA levels as actionable indicators of allograft rejection, allowing earlier administration of immunosuppression to prevent TRAL.…”

Value of cemiplimab in progressive metastatic cutaneous squamous cell carcinoma after kidney transplantation: a case report

“…Only recently, repetitive measurement of quantitative donorderived cell-free DNA (dd-cfDNA) blood levels has been identified an useful biomarker for detecting allograft injury and rejection among anti-PD-1 ICI treatment in a kidney transplant patients. 5 This promising biomarker should be evaluated in a broader study setting, as it holds a high potential for better monitoring of kidney transplants under ICI treatment. High dd-cfDNA levels may indicate high risk of allograft rejection and could thus help to identify the optimal time point of discontinuation of anti-PD-1 ICI in hopes of retaining the transplanted organ.…”

“…Only recently, repetitive measurement of quantitative donor‐derived cell‐free DNA (dd‐cfDNA) blood levels has been identified an useful biomarker for detecting allograft injury and rejection among anti‐PD‐1 ICI treatment in a kidney transplant patients 5 . This promising biomarker should be evaluated in a broader study setting, as it holds a high potential for better monitoring of kidney transplants under ICI treatment.…”

Immune checkpoint inhibitors for solid organ transplant recipients: clinical updates

“…Hurkmans et al [ 21 ] reported that after initiation of nivolumab treatment for cSCC after kidney transplant, dd-cfDNA increased to 23%, which coincided with renal function deterioration and biopsy-proven acute rejection of the allograft. In contrast, Lakhani et al [ 22 ] reported that after 10 months of treatment with pembrolizumab for melanoma, dd-cfDNA increased slightly (<0.7%) from below the detection limit (<0.19%), but did not exceed the 1% threshold suggestive of acute rejection. These findings suggest that the treatment of melanoma with pembrolizumab can be successful without evidence of allograft dysfunction or rejection.…”