Anti-PD-1 immunotherapy for the treatment of metastatic urothelial carcinoma in a kidney transplant recipient: a case report

Abstract

Background

Immune checkpoint inhibitor (ICI) therapy has been widely investigated in urothelial carcinoma; however, the utility of ICI therapy in the treatment of organ transplant recipients with metastatic urothelial carcinoma (mUC) is unclear. We herein report the first case of a first-line anti-programmed cell death-1 (anti-PD-1) monotherapy for a kidney transplant patient with mUC.

Case presentation

A 71-year-old woman who received a kidney transplant in 2003 was diagnosed with urothelial carcinoma in 2018. After operation of the tumor, the patient developed local recurrence at the site of the right kidney and bladder and multiple distant metastases in May 2020. Considering the intolerance of chemotherapy and high tumor mutation burden, we administered the anti-PD-1 agent tislelizumab (200 mg every three weeks). Partial response was achieved after two cycles of therapy and sustained until 18th cycles. There were no signs of kidney graft rejection. The immunotherapy was temporarily stopped after the 18th course because of a suspicious immune-related pneumonitis and was continued in December 2021.

Conclusions

This case demonstrates the feasibility of safely achieving stable cancer control in a kidney transplant patient with mUC without encountering graft rejection by using single-agent anti-PD-1 treatment.

Background

Urothelial carcinoma (UC) is one of the most common cancers worldwide, with over half a million new cases and a death rate of 4.2 per 100,000 person-years in 2020 [1]. Platinum-based chemotherapy has been the standard treatment for metastatic UC (mUC) for decades; however, this treatment is associated with a median overall survival (OS) of only 9.1–14.3 months [2, 3]. Advancements in immunotherapy have revolutionized mUC therapy with impressive survival benefits [4]. Immune checkpoint blockade using antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), and programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1), can enhance T-cell activity to improve anti-tumor immunity. Various immune checkpoint inhibitors (ICIs), such as the PD-1 antibodies nivolumab and tislelizumab, and the PD-L1 inhibitor avelumab, are currently employed in treating mUC based on the results of phase 2 or 3 clinical trials [5–7]. These ICIs increase the OS to approximately 21 months [7].

Kidney transplant recipients have a higher incidence of UC and worse prognosis compared to the general population, especially in Asian countries [8, 9]. However, these patients are often excluded from ICI studies due to the concern that their immunosuppressive therapy may impair the efficacy and safety of immunotherapy [5, 7]. According to previous case studies [10, 11], 40% of cancer patients who had a prior kidney transplant were expected to develop acute allograft rejection after ICI treatment, and the overall objective response rate (ORR) was approximately 30%, indicating that checkpoint blockade combined with comprehensive monitoring and management of adverse events may improve cancer outcomes in transplant recipients. Several cases [12, 13] have shown that treating transplant patients with ICIs results in both satisfying cancer response and preserved graft function. However, there are no guidelines for optimal immunotherapy in post-transplant settings. Moreover, except for one report [14] on the successful use of combined anti-PD-1 and anti-cancer therapy in a kidney transplant patient diagnosed with mUC, no published work has described anti-PD-1 monotherapy in similar patients without encountering acute rejection.

Herein, we report the first case of a kidney transplant patient with mUC who achieved partial tumor regression following first-line anti-PD-1 immunotherapy with tislelizumab.

Case presentation

A 71-year-old Chinese woman was diagnosed with kidney failure caused by chronic kidney disease in March 2003 and received a deceased donor kidney transplant in December 2003. Her posttransplant immunosuppression was maintained with cyclosporine (50 mg, twice daily, target trough level: 50–150 ng/mL), imidazolibine (50 mg, daily), and prednisone (5 mg, daily). She was then monitored regularly with no evidence of allograft rejection.

In July 2018, the patient presented with gross hematuria. Computed tomography (CT) of the abdomen and pelvis revealed a 1-cm cauliflower-like tumor on the right ureteral orifice. She subsequently underwent transurethral resection of bladder tumor, and pathology confirmed a diagnosis of high-grade noninvasive papillary UC. Since further imaging revealed a mass in the right renal pelvis, suggesting malignancy, a nephroureterectomy and bladder cuff excision were performed in February 2019. Pathology showed invasive UC of the renal pelvis and ureter, breaking through the kidney capsule, with vascular invasion, indicating pathological stage III UC (pT3N0M0, the American Joint Committee on Cancer Staging Manual 8th edition). There was no adjuvant treatment after the surgery. In May 2020, the patient came to our clinic with a growing palpable tumor located in the right lower back (Fig. 1A). CT scan revealed multiple recurrent soft-tissue masses at the site of the right kidney and urinary bladder, and suspected metastases in the right lower back, retroperitoneal lymph nodes, liver, lung, and bone (cT4N0M1, stage IV; Fig. 2A). A cyst was also noted in the transplanted kidney. An 825-gene next-generation sequencing panel performed in previous tumor tissue samples detected 94 mutations in 80 genes, with microsatellite stability, a tumor mutation burden (TMB) of 55.4 mutations per megabase, and negative PD-L1 expression.

Fig. 1.

Change in the mass in the right lower back. (A) The progressive tumor was hard and painful with dimensions of approximately 10 cm × 5 cm and local skin redness and swelling in May 2020. (B) The tumor disappeared in November 2020

Fig. 2.

CT images. (A) Before the initiation of anti-PD-1 treatment, CT scan revealed metastases in the lung, right lower back, liver, and urinary bladder (yellow arrows). (B) After two cycles of treatment, CT scan showed significant reduction of metastases. (C) After six cycles of treatment, the mass of the metastases showed further shrinkage. After (D) one year (May, 2021) and (E) 1.5 years (September, 2021) of treatment, the CT scans showed no disease progression. The lung window showed pulmonary edema with patchy shadows and ground glass opacities

Given that the patient had an Eastern Cooperative Oncology Group performance status score of 3, the multidisciplinary team determined that she could not tolerate chemotherapy. Upon comprehensive discussion with the patient and her family on the potential risks and benefits of ICI therapy, tislelizumab, an anti-PD-1 antibody, was initiated at a dose of 200 mg every 3 weeks in July 2020. Her baseline creatinine was 72 µmol/L, proteinuria was 280 mg/L, plasma cytomegalovirus (CMV) DNA level was < 500 copies/mL, Epstein-Barr virus (EBV) DNA was < 500 copies/mL, and BK virus (BKV) DNA was < 2000 copies/mL at the time of initiation of ICI. The trough level of cyclosporine was 88.9ng/mL.

After two cycles of therapy (Fig. 2B), her CT scan demonstrated partial response, which was sustained after six cycles of therapy (Fig. 2C). The mass on her back disappeared in November 2020 (Fig. 1B). Graft function remained stable during anti-PD-1 treatment with a serum creatinine level between 72 and 115 µmol/L and low-level proteinuria at approximately 0.3 g/L (Fig. 3). Ultrasound of the transplanted kidney was performed with no abnormal findings. Serum creatinine was slightly elevated, so the immunosuppressants were maintained with no change. The actual cyclosporine trough level was controlled at 97.5-123.4 ng/mL. A grade 2 adverse event (immune-related rashes on both legs) was observed (Fig. 4) and resolved with antihistamines and topical corticosteroids. Surveillance imaging was carried out every 3 to 4 months until September 2021, indicating no disease progression (Fig. 2D and E). After the 18th course of tislelizumab, the patient began to complain of progressive cough, shortness of breath, and fever, and developed respiratory failure. Arterial blood gas analysis under room air showed pH of 7.39, pCO2 of 35.5 mmHg, pO2 of 53.7 mmHg, SO2 of 87%, BE of -1.81 mmol/L, and HCO3- of 21.8 mmol/L. CT of the chest demonstrated pulmonary edema with bilateral patchy ground glass opacities (Fig. 2E). The serum creatinine level at that time was 86 µmol/L. The local hospital considered that her pneumonia was a result of infection rather than immune-related adverse events. The patient received non-invasive ventilation and was treated with cefoperazone and methylprednisolone (40 mg, daily) in the intensive care unit until all symptoms were brought under control. In our clinic, out of concern for possible immune-related pneumonitis, which was assessed as a grade 4 adverse event, the immunotherapy was discontinued, prednisone was increased to 1 mg/kg daily, and trimethoprim-sulfamethoxazole was used as a prophylactic antibiotic. After the CT lesions were completely absorbed (CT was not available in the local hospital), tislelizumab was continued in December 2021.

Fig. 3.

Serum creatinine and urine protein levels during treatment

Fig. 4.

Images showing a grade 2 adverse event (immune-related rashes) on the (A) right and (B) left leg during treatment

Discussion and conclusions

UC is a common malignant tumor seen in urology. Although chemotherapy has long been the first-line treatment option for patients with mUC [2, 3, 15], its effects are limited. The rapid development of immunotherapy agents targeting PD-1/PD-L1 has changed the treatment landscape of mUC. At present, there are six ICIs approved for treating mUC worldwide, including four agents approved by Food and Drug Administration, nivolumab [5], avelumab [7], pembrolizumab [16], and atezolizumab [17], and the other two approved in China, tislelizumab [6] and toripalimab [18]. Tislelizumab was approved in April 2020, bringing meaningful clinical benefits to the Chinese population [19]. Ye et al. [6] demonstrated that tislelizumab as a non-first-line treatment had significant antitumor activity in patients with locally advanced UC or mUC. The overall ORR was 24.8%, the disease control rate (DCR) was 38.6%, and the median OS and progression-free survival (PFS) times were 9.8 and 2.1 months, respectively. In an ongoing phase 3 clinical trial, Bi et al. [20] is comparing the combination of tislelizumab and platinum-gemcitabine chemotherapy to a placebo plus chemotherapy in the first-line treatment of patients with advanced UC (ClinicalTrials.gov ID: NCT03967977, Registration Date: 2019.5.30); the results have not been published yet. In the JAVELIN Bladder 100 trial, Powles et al. [7] found a median OS of 21.4 months in patients receiving maintenance avelumab after effective chemotherapy. In the IMvigor130 trial, Galsky et al. [21] reported a PFS of 8.2 months and an OS of 16.0 months in patients receiving atezolizumab plus chemotherapy, and a median OS of 15.7 months in those receiving atezolizumab monotherapy as first-line mUC treatment. The use of immunotherapy agents in first-line treatment for UC [15], including combination of ICIs with chemotherapy [20, 21], single-agent immunotherapy [16, 17, 21], and maintenance immunotherapy [7], requires further investigation.

UC patients with high TMB may benefit from immunotherapy, as previously reported [22], and TMB is widely accepted as a biomarker for predicting clinical response to immunotherapy. Chen et al. [23] reported a kidney transplant recipient with mUC who had a relatively high TMB of 66.44 mutations per megabase, similar to the TMB in our case (55.4 mutations per megabase). Therefore, we hypothesized that organ transplant recipients who develop post-transplant malignancies tend to have high TMB. Although there is little evidence to support our hypothesis, TMB has been confirmed to be significantly associated with cancer risk in solid organ transplant patients [24].

However, it should be noted that patients with organ transplantation were excluded in previous clinical trials of ICI. The overactivation of immune T cells may lead to autoimmune diseases, and the PD-1 and CTLA-4 signaling pathways play important roles in down-regulating the activity of the immune system. Both of these signaling pathways are also involved in the immune tolerance of organ transplants. As a result, ICIs may accelerate graft-versus-host disease due to the inhibition of the PD-1 and CTLA-4 signaling pathways [25].

Although organ transplant recipients were excluded from past ICI clinical trials, there is some relevant literature on the subject. De Bruyn et al. [26] reviewed 48 cases of organ transplant recipients treated with ICIs. The ORR and DCR in all patients were 31% and 35%, respectively, while the ORR, DCR and graft rejection incidence in renal transplant recipients were 38%, 45%, and 45%, respectively. In a retrospective analysis [27], out of 12 transplant patients (most of whom were kidney transplant patients), four experienced organ rejection. In a case study of 17 organ transplantation cases, including kidney, liver, and heart recipients, Oweyemi and colleagues [28] found that five (29%) experienced an adverse event, three (18%) had acute allograft rejection, and the median duration on ICIs was 1.7 months. However, these studies provided little data for UC patients treated with anti-PD-1 drugs. Previously published cases of immunotherapy in transplant recipients with UC are summarized in Table 1 [14, 23, 29]. Chen et al. [23] reported a complete mUC response in a kidney transplant patient who received three cycles of nivolumab treatment alone after failure of chemotherapy and radiotherapy. Nevertheless, the patient developed graft rejection, which led to renal failure and immunotherapy withdrawal. In a case report in Taiwan [14], a patient with UC after renal transplantation was treated with a combination of pembrolizumab, bevacizumab, cisplatin, and gemcitabine, and showed partial response after 11 cycles of treatment with intact graft function, similar to our case. In our case, the patient was diagnosed with UC 15 years after renal transplantation. Due to chemotherapy intolerance and high TMB, she received immunotherapy after full communication with her family. As the only approved ICI for mUC in China at that time, tislelizumab was chosen for this patient with negative PD-L1 expression. Indeed, as known, tislelizumab is usually applied to PD-L1 overexpressed mUC [6]; however, responses to tislelizumab were observed in UC patients regardless of PD-L1 expression in previous studies [28, 30], with an ORR of 24% for PD-L1 positive and 21% for PD-L1 negative [19]. The result of our case indicates that immunotherapy can be considered carefully in organ transplant recipients based on biomarkers such as TMB. Meanwhile, the immunogenicity of specific organ transplants, the selection of the specific ICIs, the interval between organ transplantation and ICI therapy, and regular monitoring of graft status all contribute to the occurrence of graft rejection [29].

Table 1.

ICIs in transplant recipients with UC

First author et al.	Date of publication	Sex	Age(y)	Type of transplant	Time from transplant to immunotherapy (y)	Immunotherapy/ doses or duration	Immunosuppression while on immunotherapy	Disease response	Graft rejection
Wu et al. [14]	2-Aug-2017	Female	61	Renal	8.3	Pembrolizumab/11 doses	Tacrolimus and mycophenolate	PR	No
Owoyemi et al. [29]	12-Aug-2020	Male	64	Heart	> 9.6	Atezolizumab/>11.5 months	Mycophenolate, cyclosporine and prednisone	SD	No
Chen et al. [23]	26-May-2021	Female	54	Renal	14	Nivolumab/3 doses	Mycophenolate	CR	Rejection a week after the 2nd dose of nivolumab

Abbreviations CR, complete remission; ICIs, immune checkpoint inhibitors; PR, partial remission; SD, stable disease; UC, urothelial carcinoma

To balance the tumor response and risk of rejection during immunotherapy in UC patients with organ transplant, immunosuppression management also becomes a challenge. Clinicians should closely monitor the organ function. It is reasonable to increase the dose of immunosuppressants appropriately when graft rejection symptoms occur [29], but increased risk of infection should also be awared of. In our case, the patient had undergone kidney transplantation for many years and the immunosuppressive agents had reached a stable dose. During the ICI treatment, there were no signs of rejection in the transplanted kidney, so the immunosuppressants remained consistent with the same target trough level throughout cancer diagnosis and immunotherapy.

Our case has firstly proved that single PD-1 inhibitor such as tislelizumab is feasible to be an effective and safe option in mUC patients with a history of kidney transplant. Future research is required to further investigate the application of ICIs in organ transplant recipients.

Abbreviations

BKV

BK virus

CMV

Cytomegalovirus

CT

Computed tomography

CTLA-4

Cytotoxic T lymphocyte antigen-4

DCR

Disease control rate

EBV

Epstein-Barr virus

ICI

Immune checkpoint inhibitor

mUC

Metastatic Urothelial Carcinoma

ORR

Objective response rate

OS

Median overall survival

PD-1

Programmed cell death-1

PD-L1

programmed cell death-ligand 1

PFS

Progression-free survival

TMB

Tumor mutation burden

UC

Urothelial carcinoma

Author contributions

HH and ZD acquired the data, reviewed the literature, and drafted the manuscript. Ziming J interpreted the radiological results and helped drafted the manuscript. XL and LM helped in the care and investigation of the patient. Zhigang J and XF guided the treatment of the patient and revised the paper. All authors approved the final version of the paper.

Funding

This study was supported by National High Level Hospital Clinical Research Funding (2022-PUMCH-A-248).

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Given the retrospective nature of the case report, institutional review board approval was waived. Consent for participation was obtained from the patient. The study was performed in accordance with the Declaration of Helsinki.

Consent for publication

The patient provided informed consent for publication.

Competing interests

The authors declare no competing interests.