The goal of any course of cancer treatment is to prevent and/or kill future growth of malignant cells. Sometimes this can be challenging as some cancer cells gain the ability to “trick” the immune system into thinking the cancer cells are normal healthy cells. Oncologists are seeing promise in immune checkpoint inhibitors (ICI), which actually “open up the immune system” and allow the immune system (T cells) to recognize and attack the cancer. Renal effects of immunotherapy are not minor. Acute interstitial nephritis (AIN), podocytopathy, and electrolyte disorders have been reported.
ICIs include the anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody, as well as anti-programmed cell death (PD-1) antibodies. These antibodies serve to enhance the innate anti-tumor T-cell immunity leading to tumor regression, as well as stabilization of solid tumors. ICI related to renal toxicity is an immune-mediated process. AIN is the most common biopsy finding reported with PD-1 inhibitors. Ipilimumab, a CTLA-4 inhibitor, is also associated with AIN; however, podocytopathies such as membranous nephropathy, minimal change disease, and thrombotic microangiopathy also have been reported.
Hyponatremia related to hypophysitis is also seen with CTLA-4 antagonists. The time of onset usually differs in the two class of agents. CTLA-4 antagonist-mediated injury usually occurs earlier within the first 2-3 months of use, while PD-1 inhibitor mediated injury is usually seen 2-10 months into treatment. Treatment usually involves interruption of therapy and treatment with high-dose steroids. It is important for the general nephrologists and oncologists to know about these effects. Two recent reviews have summarized the effects of ICIs on the kidney (Am J Nephrol 2017;45(2):160-169, Nephrol Dial Transplant 2016; doi:10.1093/ndt/gfw382).
Immune Checkpoint Inhibitors & Kidneys
While effective in most cancer patients, this course of treatment has been less successful in kidney transplant patients because activating the immune system causes the patient's body to start rejecting their donor kidney. As summarized in a recent review, five prior cases published in the literature of renal transplant patients getting PD-1 inhibitors have resulted in rejection (J Onco-Nephrol 2017;1(1):42-48).
The first reported cases of kidney transplant patients receiving ICI involved two patients with metastatic melanoma who received the CTLA-4 antagonist ipilumumab (J Clin Oncol 2014;32(19):e69-71). Renal allografts in both patients were unaffected by ipilumumab, and the patients had excellent anti-tumor response to the immunotherapy.
In contrast, four cases of renal allograft loss have been associated with nivolumab and pembrolizumab, which are both PD-1 inhibitors (N Engl J Med 2016;374(9):896-898, Am J Transplant 2016;16(4):1332-1333, Ann Oncol 2016;27(6):1135-1137, Am J Transplant 2016;16(8):2496-2497). Two received PD-1 inhibitor therapy (pembrolizumab and nivolumab) shortly after the CTLA-4 inhibitor ipilimumab (i.e., they received combination treatment with CTLA-4 and a PD-1 inhibitor). Graft loss, which occurred days to weeks following PD-1 inhibitor administration, was due to T-cell-mediated (Banff type IIA or IIB) or cellular- and antibody-mediated acute rejection (N Engl J Med 2016;374(9)896-898, Am J Transplant 2016;16(4):1332-1333, Ann Oncol 2016;27(6):1135-1137, Am J Transplant 2016;16(8):2496-2497).
Herz, et al, reported the case of a renal transplant patient with baseline creatinine in 1.7 mg/dL who received both CTLA-4 and PD-1 inhibitors for metastatic melanoma and did not have a rejection episode (Eur J Cancer 2016;67:66-72). In that particular case, the immunosuppression was not altered and the patient was continued on tacrolimus and prednisone. While graft loss was not observed, the melanoma progressed. One relevant point is related to how the maintenance immunosuppression is managed.
Organ transplant centers may have different approaches with regard to the reduction of immunosuppression after cancer diagnosis, which may interfere with events such as rejection. Pre-clinical studies have suggested the importance of PD-1 and its ligands in influencing allograft adaptive tolerance to transplants (Am J Transplant 2012;12(10):2575-2587).
The four cases of rejection were the first to demonstrate the relevance of the PD-1 pathway in maintaining tolerance in solid organ transplants (N Engl J Med 2016;374(9):896-898, Am J Transplant 2016;16(4):1332-1333, Ann Oncol 2016;27(6):1135-1137, Am J Transplant 2016;16(8):2496-2497). Interestingly, these findings suggest the functional difference between CTLA-4 and PD-1; the latter is more important in immunomodulation within peripheral tissues. Based on the seven cases, it appears PD-1 inhibitors could be more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists, especially when the patients have received anti-CTLA-4 agents prior to PD-1 inhibitor treatment and have limited immunosuppression on board (N Engl J Med 2016;374(9):896-898, Am J Transplant 2016;16(4):1332-1333, Ann Oncol 2016;27(6):1135-1137, Am J Transplant 2016;16(8):2496-2497, Eur J Cancer 2016;67:66-72). This may be related to the key regulatory role of PD-1 in preventing allospecific T cells from proliferating and becoming activated in the secondary lymphoid organs.
In addition, the blockade of PD-1/PD-L1 interaction may also affect the immune response in the graft itself; for example, by blocking the inhibitory signal from renal tubular cells or endothelium cells to effector T cells (Kidney Int 2010;78(1):38-47). This peripheral immune regulatory network plays an essential role in maintaining graft tolerance and minimizing the chance of rejection (Kidney Int 2010;78(1):38-47).
Patient Case Study
In a recent case correspondence (N Engl J Med 2017;376(2):191-192), the authors observed during the treatment of a patient with cancer who also had a kidney transplant and was on combination of steroids and sirolimus (an immunosuppressant that blocks mammalian target of rapamycin and has anti-cancer properties), that he did not experience rejection during cancer treatment with ICI. It is possible sirolimus prevented rejection or the patient was so immunocompromised by his cancer he did not reject his kidney.
In the case, the authors observed the treatment of a 70-year-old Caucasian male who received a kidney transplant in 2010 and recently underwent treatment for small bowel cancer that had spread to the liver. The patient was given prednisone and sirolimus prior to incorporating an ICI (nivolumab). The steroids were started 1 week prior to starting nivolumab and continued at a tapered regimen as mentioned in the manuscript to prevent the immune-mediated reaction seen in prior cases. Steroids didn't hinder the shrinkage of the cancer. There was significant response in tumor burden and the serum creatinine remained stable (N Engl J Med 2017;376(2):191-192). There were no clinical or immunological signs of rejection.
Given the above case report, can this preventive strategy be applied to other organ transplant patients receiving PD-1 inhibitors? It is too early to tell. More experience and large trials are needed to answer that question.
KENAR D. JHAVERI, MD, is Professor of Medicine, Hofstra Northwell School of Medicine, Hofstra University, Hempstead, N.Y.