Use of the PD-1 Pathway Inhibitor Nivolumab in a Renal Transplant Patient With Malignancy (2016)

To the Editor: Programmed cell death protein 1 (PD-1) is a receptor found on T cells, and when bound with its ligand PD-L1 or PD-L2, it negatively regulates T cells. Certain tumors, such as squamous non–small cell lung cancer and melanoma, evade T cell immune surveillance by upregulating PD-1 ligands. Blockade of PD-1 and its ligand can restore T cell–mediated tumor suppression (1Postow MA Callahan MK Wolchok JD Immune checkpoint blockade in cancer therapy.J Clin Oncol. 2015; 33: 1974-1982Crossref PubMed Scopus (1839) Google Scholar). A 74-year-old white male renal transplant recipient with stage IV squamous non–small cell lung cancer underwent a biopsy for an acute elevation in serum creatinine to 7.5 mg/dL from a baseline of 0.75 mg/dL. The patient had received three doses of nivolumab, a human IgG4 monoclonal antibody that binds to PD-1. The patient's end-stage renal disease was secondary to diabetes mellitus and hypertension, and the allograft had been in place for 3 years before the diagnosis of malignancy. The maintenance immunosuppression for this patient was a two-drug regimen of cyclosporine and prednisone. Subsequent to his diagnosis of a malignancy, his cyclosporine dose was decreased to maintain a goal trough level less than 50 ng/mL. His trough level for the next 2 years remained below the goal range without any evidence of renal dysfunction, until the initiation of nivolumab. Donor-specific antibody testing was not performed. The biopsy showed severe rejection, including acute vascular rejection (Banff type IIB) with associated severe lymphocytic tubulitis, diffuse interstitial hemorrhage, positive C4d staining of peritubular capillaries, and microcirculation inflammation (Figure 1). The rejection was treated with prednisone and dialysis. Research from the transplant perspective indicates the importance of PD-1 signaling as an immune checkpoint to maintain graft tolerance (2Riella LV Paterson AM Sharpe AH Chandraker A Role of the PD-1 pathway in the immune response.Am J Transplant. 2012; 12: 2575-2587Crossref PubMed Scopus (285) Google Scholar,3Tanaka K Albin MJ Yuan X et al.PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.J Immunol. 2007; 179: 5204-5210Crossref PubMed Scopus (149) Google Scholar). It is possible that the nivolumab altered T cell function through blockade of the PD-1 pathway and contributed to the development of allograft rejection. Although the biopsy showed a combination of cell-mediated and antibody-mediated rejection, the interplay between T cell and B cell function should not be negated. The practice of immunosuppression reduction in solid organ transplant recipients with malignancies is variable. This patient did have his immunosuppression reduced and that may have contributed to the rejection episode. However, given the temporal association with this patient's rejection and knowing the protective role of PD-1 signaling for allograft tolerance (2Riella LV Paterson AM Sharpe AH Chandraker A Role of the PD-1 pathway in the immune response.Am J Transplant. 2012; 12: 2575-2587Crossref PubMed Scopus (285) Google Scholar,3Tanaka K Albin MJ Yuan X et al.PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.J Immunol. 2007; 179: 5204-5210Crossref PubMed Scopus (149) Google Scholar), we propose that chemotherapeutic agents that block the PD-1 signaling pathway be studied further and that multidisciplinary collaboration occur in this patient population to help the patient consider the risks and benefits of treatment. There are no contraindications to nivolumab listed, with warnings including immune-mediated nephritis or renal dysfunction. This chemotherapeutic agent was not specifically evaluated in solid organ transplant recipients. The loss of a solid organ transplant is a devastating complication that can become irreversibly life threatening. It is imperative to consider the risks and benefits of novel chemotherapeutic agents, especially in this patient population. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.