Antitumor activity of nivolumab on hemodialysis after renal allograft rejection

Abstract

BackgroundNivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer.Case presentation We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient’s immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response.ConclusionsThis case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis.

Immune checkpoint inhibitors in the management of malignancies in transplant recipients

“…In these cases, ciclosporin7 and tacrolimus,13 respectively, were discontinued before administering ipilimumab and were maintained on prednisone. In the next two reports, patients with melanoma were treated with pembrolizumab,6 and nivolumab 14. In the first case,6 the patient was on the immunosuppressive regimen (mycophenolate, tacrolimus) which was discontinued and started on a regimen of (everolimus, azathioprine) before initiating pembrolizumab and subsequently underwent graft rejection with the progression of melanoma.…”

“…In the first case,6 the patient was on the immunosuppressive regimen (mycophenolate, tacrolimus) which was discontinued and started on a regimen of (everolimus, azathioprine) before initiating pembrolizumab and subsequently underwent graft rejection with the progression of melanoma. In the second case,14 tacrolimus and MMF (mycophenolate mofetil ) were discontinued and started on prednisone before initiating nivolumab with the patient having a graft rejection, but with partial tumour response.…”

“…Interestingly, this T-cell response to kidney allograft antigens can be downregulated by the expression of PD-L1 on the tubular epithelium of kidney 40. Thus, PD-L1 expression patterns on renal allografts may determine the risk of rejection due to PD-1 inhibitors 14. But, unfortunately, no studies until now have adequately identified the connection between the expression patterns of PD-L1 and the risk of rejection 14.…”

“…Thus, PD-L1 expression patterns on renal allografts may determine the risk of rejection due to PD-1 inhibitors 14. But, unfortunately, no studies until now have adequately identified the connection between the expression patterns of PD-L1 and the risk of rejection 14. Anyway, it has been shown that higher PD-1 expression on T-cells is associated with an enhanced risk of rejection 41.…”

“…Liver transplant patients showed both cellular and antibody-mediated rejection following anti-PD1 inhibitor therapy and also the grafts expressed PD-L1 implicating its role in the rejection 34. Finally, it is also important to consider the consequences of graft rejection, for example, in the postrenal transplant setting, there is the option for haemodialysis as rescue,14 whereas it is possible that immunotherapy in other solid organ transplant patients like heart, liver, lung is potentially more dangerous as there is no 'rescue' option such as haemodialysis.…”