Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?

Abstract

Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients.

Intratumoral immunotherapy with anti-PD-1 and TLR9 agonist induces systemic antitumor immunity without accelerating rejection of cardiac allografts

“…One of the most promising cancer therapies developed in the last decade is the immune checkpoint inhibitors targeting the PD-1 and CTLA-4 pathways. [4][5][6]17 It remains to be established whether these agents can be safely administered to transplant recipients with ma- [21][22][23] However, despite achieving significant anti-tumor activity, i.p.…”

“…Similar results have been reported in experimental models and in clinical patients. [6][7][8][9][10][11]16 It seems that the alloimmune tolerance is more prone to systemically enhanced innate and adaptive immune responses, [6][7][8][9][10][11] while tumors showed relative resistance to these responses likely due to the presence of immune inhibitory microenvironment. 16 including APCs and T cells and development of effector CTLs.…”

“…5 However, there is a growing concern whether PD-1 inhibitors can be administered safely to transplant recipients with advanced cancer because T cells activated by checkpoint inhibitors may become reactive not only toward tumor antigens but also toward donor alloantigen, thereby resulting in allograft rejection. [6][7][8][9][10][11] Thus the use of PD-1 inhibitors in transplanted recipients with advanced cancer is limited because of an associated risk of graft rejection. This is especially unfortunate given the high incidence of malignancies in transplant patients under immunosuppression.…”

“…lignancies. Because of the many similarities in the mechanisms of action between transplant immunosuppression and cancer immunomodulation, solid organ transplant recipients have been excluded from checkpoint inhibitory clinical trials because of the concern of provoked alloreactive immunity and possible organ graft rejection, and several case reports showed acute organ rejection during checkpoint inhibitory therapy [6][7][8][9][10][11]. The use of immunosuppressants is as-sociated with an increased risk of cancer, consequently it is critical F I G U R E 6 Specificity of intratumoral (i.t.)…”

The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?

“…Regard the rejection type, acute rejection of transplanted kidney after PD-1 inhibitors occurs mainly through T cell mediated rejection, although antibody mediated rejection has been also observed ( 89 ).…”