Checkpoint Inhibitors in Kidney Transplant Recipients and the Potential Risk of Rejection

To the Editor: Enhancing anti-tumor T cell immunity with checkpoint inhibitor antibodies such as anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-program death 1 (PD-1) has shown significant clinical benefits in tumor regression and prolonged stabilization of non–small cell lung cancer, melanoma, and renal cell cancer (1.Motzer RJ Escudier B McDermott DF Nivolumab versus everolimus in advanced renal-cell carcinoma.N Engl J Med. 2015; 373 (et al): 1803-1813Crossref PubMed Scopus (4106) Google Scholar, 2.Topalian SL Hodi FS Brahmer JR Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012; 366 (et al): 2443-2454Crossref PubMed Scopus (9275) Google Scholar). Clinical trials of CTLA-4 and PD-1 antibodies excluded patients receiving immunosuppression medications for organ transplantation (3.Hodi FS O’Day SJ McDermott DF Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363 (et al): 711-723Crossref PubMed Scopus (11191) Google Scholar). Therefore, the adverse events related to CTLA-4 and PD-1 antibody treatment in kidney transplant recipients with metastatic cutaneous melanoma have not been examined. We report a 68-year-old white male former smoker (36 pack years, quit 2006) who had a history of kidney disease secondary to autosomal dominant polycystic kidney disease and who underwent a deceased donor kidney transplantation in 2000 (1A, 1B, 0 DR HLA mismatch). Initial immunosuppression medications were cyclosporine, azathioprine, and prednisone. Posttransplant he developed multiple skin cancers including squamous cell carcinoma and cutaneous melanoma that were surgically excised. He was diagnosed with squamous cell carcinoma of unknown primary with metastases to lung and bone 5 years posttransplantation, and azathioprine was discontinued. He received carboplatin and paclitaxel chemotherapy with complete response. Positron emission tomography–computed tomography imaging confirmed complete regression of the lung and osseous sites of disease. In April 2015, the patient developed metastatic melanoma with extensive inguinal, iliac, and aortocaval adenopathy deemed unresectable. Biopsy of the inguinal node confirmed metastatic melanoma and no BRAF mutation was detected. Cyclosporine was discontinued and the patient was treated with four doses of ipilimumab (CTLA-4 antibody) 3 mg/kg every 3 weeks. Restaging showed interval progression with increase in the size of retroperitoneal and inguinal adenopathy. Two weeks after the last dose of ipilimumab, pembrolizumab (anti-PD-1 antibody) was initiated with a stable baseline serum creatinine of 1.1 mg/dL. Three weeks later and prior to the second dose, serum creatinine increased to 8.7 mg/dL. A kidney allograft biopsy revealed mixed acute cellular rejection (severe tubulitis t3, severe interstitial inflammation i3, and intimal arteritis v1; BANFF grade IIa), acute antibody-mediated rejection, and areas of cortical necrosis. The patient was treated with methylprednisolone 500 mg for 3 doses and low-dose once-a-day tacrolimus was started. Kidney function slightly improved, but the patient ended up on hemodialysis. Blockade of CTLA-4 and PD-1 increases the activation of T cells, not only against malignant cells, but also other cells expressing foreign antigen such as kidney allograft donor antigens. This T cell activation could lead to acute cellular rejection and the activated CD4 T cells might lead to B cell proliferation and activation through costimulatory ligands (e.g. CD40L) and cytokines (e.g. IL-4, IL-21, and interferon-γ) leading to antibody-mediated rejection, especially in the setting of immunosuppression withdrawal (4.Hoffman W Lakkis FG Chalasani G. B cells, antibodies, and more.Clin J Am Soc Nephrol. 2016; 11: 137-154Crossref PubMed Scopus (222) Google Scholar). B cells can also be activated as a direct effect on memory B cells expressing PD1 if there were prior sensitization of the transplanted organ or a decrease in immunosuppressive medications. Typical management of advanced melanoma in kidney transplant recipients includes aggressive reduction of immunosuppression medication that is tailored according to patient age, HLA mismatch level, time after transplantation, and history of rejection (5.Zwald FO Christenson LJ Billingsley EM Melanoma in solid organ transplant recipients.Am J Transplant. 2010; 10 (et al): 1297-1304Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Treatment of advanced melanoma with PD-1 inhibitors (such as pembrolizumab and nivolumab) results in a higher rate of tumor regression than in patients receiving CTLA-4 antibodies such as ipilimumab. The timing of rejection in our case seems to be secondary to anti-PD-1 inhibition, although the possibility of combined dual checkpoint inhibition cannot be completely excluded since the patient recently completed a full course of anti-CTLA-4 treatment with four doses of ipilimumab. The transplant community should be aware of the potential risk of rejection in kidney transplant recipients with the use of checkpoint inhibitor antibodies. Close monitoring of kidney function and moderate reduction of immunosuppression are warranted. Conversion of tacrolimus to mammalian target of rapamycin inhibitors and increasing prednisone to 10 mg daily may be a reasonable alternative regimen that might prevent rejection and would not be expected to limit the efficacy of CTLA-4 or PD-1 antibodies against the melanoma, but there are no data to support that. Ultimately, we need to realize that checkpoint inhibitor antibodies are lifesaving treatments, particularly in metastatic melanoma. However, the benefits of tumor regression versus the potential risk of allograft rejection and allograft loss should be weighed carefully for each individual patient. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.