Immune checkpoint inhibitors in liver transplant recipients - a review of current literature

INTRODUCTION

Hepatocellular carcinoma (HCC) is the primary liver tumor and the fourth leading cause of cancer-related death worldwide^[1]. Incidence of this disease has steadily increased over the last several years^[2]. Established surveillance guidelines have enabled the detection of HCC at an earlier stage. Still, despite these guidelines, a significant number of patients are diagnosed with HCC at an advanced stage when curative therapies are not an option. Systemic chemotherapy using sorafenib was the only standard of care available for patients with advanced HCC for several years; however, multiple alternative agents have now been approved as first line, including lenvatinib. Various second-line therapies have also been approved for HCC; these include several immune checkpoint inhibitors (ICIs), which fall under the broader category of immuno-oncology. While there is an established role for ICIs in advanced disease, there are no clear guidelines or protocols for their use in the peri-transplant setting. There is a higher risk of de novo malignancies in liver transplant recipients on immunosuppression. These include skin cancer (with an increased risk of up to 70%); lung, colorectal, and kidney cancers; and recurrent HCC^[3]. The role of IO in many of these malignancies is well established in non-transplant patients, but data is limited in solid organ transplant recipients.

The primary concern for the peri-transplant use of ICI is the risk of graft rejection. It is believed that the programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) pathways facilitate immune tolerance of the graft; PD-L1 is expressed in post-transplant liver allografts and PD-1 is heavily expressed on graft-infiltrating T-cells^[4,5]. Similarly, binding of CTLA4 on T-cells to its counter-receptor B7 provides an inhibitory signal that terminates T-cell responses^[6,7]. Hence, blockade of these pathways may trigger prolific activity of these T-cells, resulting in a T-cell mediated graft rejection. However, based on the limited body of evidence we have reviewed, we hypothesize that there are certain favorable conditions in which ICI use may lend to a decreased chance of graft rejection.

In this review, we will discuss the role of ICI’s in the peri-transplant setting, their safety, and their efficacy.

IMMUNE CHECKPOINT INHIBITOR THERAPY PRE-TRANSPLANT

Patients with HCC diagnosed beyond Milan criteria are often treated locoregionally with radiofrequency ablation, transarterial chemoembolization (TACE), or transarterial radioembolization^[8]. There is a growing interest in combining systemic with locoregional therapy to downstage these patients and make them eligible for liver transplant (LT)^[9]. However, there are limited data on the role of neoadjuvant systemic treatment, including IO in the liver transplant setting. Sorafenib was FDA-approved for treating patients with advanced HCC in 2008, based on a modest improvement in overall survival (OS) compared to placebo (10.7 months vs. 7.9 months)^[10]. Thereafter, the advanced HCC therapeutic arsenal expanded past sorafenib to include lenvatinib and combined atezolizumab plus bevacizumab as first line therapy and tyrosine kinase inhibitors regorafenib and cabozantinib and ICIs nivolumab and pembrolizumab as second line therapy^[11]. However, to date, only sorafenib has been studied in the neoadjuvant setting, but prospective trials have failed to demonstrate any benefit in OS or disease outcome according to RECIST criteria^[12,13].

Now that ICIs have a niche in the standard treatment algorithm for advanced HCC^[11], there is growing interest in their neoadjuvant use prior to LT. So far, only two case reports have been published in this domain. First, Nordness et al.^[14] reported a case of poor outcome in a 65-year-old male with HCC within Milan criteria, who quickly failed sorafenib therapy and was initially declined a LT due to up-trending blood alpha fetoprotein (AFP) levels. These levels reached as high as 2500 ng/mL when the patient began treatment with nivolumab (intended as a destination therapy) for almost 2 years before undergoing TACE. This ICI plus TACE strategy maintained the patient’s disease within Milan criteria, reducing his AFP levels to 2.3 ng/mL and allowing him to undergo LT 8 days after his last dose of nivolumab. The patient’s postoperative course, which included a standard immunosuppressant drug regimen of tacrolimus, mycophenolate, and prednisone, was unfortunately complicated by signs of profound liver injury on postoperative day (POD) 2. A liver biopsy on POD 6 demonstrated acute hepatic necrosis with profound lymphocyte infiltration, consistent with graft rejection. Despite the initiation of high-dose immunosuppression (methylprednisolone 1000 mg/day and rabbit anti-thymocyte globulin, he expired on POD 10.

In another case reported by Schwacha-Eipper et al.^[15], a 65-year-old male had a good outcome with neoadjuvant nivolumab followed by LT. He was diagnosed beyond Milan criteria and was started on nivolumab after progression on sorafenib for 14 months. He continued nivolumab for 34 cycles (> 1 year) and had a good partial response with successful downstaging of his cancer, after which he was reevaluated for LT. Due to concern over nivolumab-induced transplant rejection, nivolumab was stopped 6 weeks before listing the patient for transplantation. He was 15 weeks out from his last nivolumab dose when he received a LT. He continues to do well without any evidence of disease recurrence when last reported, one year after surgery.

Given the low sample size, we can only conclude from the two cases reported here that downstaging of HCC for transplant via neoadjuvant IO is feasible in a select population, although the risk of graft rejection poses a real concern. One of the glaring differences between these cases is the timing of the last dose of nivolumab with respect to liver transplantation. A shorter period between the last dose of ICI and LT (8 days vs. 15 weeks) may increase the risk of graft rejection. The long-lasting effects of ICIs have been well described. In HCC, pembrolizumab had a median duration of response (DOR) of 13.8 months in KEYNOTE-240, while nivolumab +/- ipilimumab had a median DOR of 17 months in CHECKMATE-040^[16-18]. The lasting effects of ICIs are supported by the delayed appearance of adverse events (AEs). The time to onset of ICI AEs varies by organ sites but is generally in the order of weeks to months. For example, the median time to hepatotoxicity is 3 to 9 weeks, and the median time to pneumonitis is about 2.5 months (but may take up to 24 months)^[19-21]. Furthermore, nivolumab and pembrolizumab have long half-lives (~25 days)^[22]. Usually, it takes 4 to 5 half-lives for plasma concentrations of any given drug to drop below clinically relevant concentrations. We hypothesize that the optimal timing of transplant after the last dose of ICI would be in the order of months, which should take a patient outside of the risk period of the majority of liver-related adverse events, possibly including toxicity to the liver graft. Even so, any lasting effects of ICIs after plasma elimination still need to be determined.

IMMUNE CHECKPOINT INHIBITOR THERAPY POST LIVER TRANSPLANT

Despite increasingly stringent criteria guiding the selection of transplant candidates (i.e., Milan criteria), recurrence of HCC occurs in up to 15%-20% of liver transplant recipients^[23-26]. Median survival after recurrence is only around 12 months^[25,26]. There is no formal consensus on the appropriate treatment at the time of recurrence. Sorafenib has been commonly used in this scenario, mostly because of concerns related to IO use in a transplant patient on immunosuppressants. However, there is growing interest in exploring IO as a treatment option in this population, especially following the recent ICI approvals for patients with advanced HCC^[16,27,28]. Graft recipients are still suspectable to the development of secondary malignancies such as melanoma and lung cancer. In one meta-analysis, investigators found that melanoma was 2.71 times more common in solid organ transplant patients and potentially related to the use of immunosuppressive therapies^[29]. Melanoma and lung cancers are now preferably treated with IO^[30,31], but, to date, there have been no formal recommendations regarding the use of IO post-transplant, although several case reports document the application of these agents in this setting.

A summary of 28 cases of liver transplant recipients who went on to receive IO is shown in Table 1; this is the most comprehensive list to date^[32-50]. HCC was the reason for LT in 22 of these cases. The most common indications for post-transplant IO were recurrent HCC (18 cases) and malignant melanoma (7 cases). Out of all 28 reviewed cases, 4 patients had a confirmed complete response (CR), and 3 had partial responses to IO. Twelve cases had progression of disease after ICI use, and 9 had unknown responses. Specifically, for those with recurrent HCC, 2 of 18 patients had complete responses, and no partial responses were described. Both HCC patients who responded demonstrated durability of these treatment effects, with CR lasting beyond the time of their respective case reports at > 10 months and > 1.5 years. Reportedly, all patients had received at least sorafenib and often had further lines of therapy for HCC prior to receiving IO. As a point of reference, investigators of the Phase II KEYNOTE-224 and phase III KEYNOTE-240 trials described an objective response rate (ORR) in non-transplant HCC patients treated with subsequent-line pembrolizumab of 17% and 18%, respectively^[17,27]. Of the 7 melanoma cases shown in Table 1, 2 patients had complete responses, and 2 had partial responses to therapy. When these response data are compared with data from non-transplant patients with advanced melanoma in the Phase III CHECKMATE-066 and KEYNOTE-006 trials, in which nivolumab and pembrolizumab monotherapy were used to treat advanced melanoma, with a ~40% ORR and ~15% CR^[51,52], it can be seen that response data are similar. Hence, recurrent HCC or melanoma in liver transplant recipients can respond to IO.

ADVERSE EVENTS

Immune checkpoint inhibitor (ICI) therapy is associated with a spectrum of adverse effects categorized as immune-related adverse events (irAEs)^[53]. These toxicities are generally considered distinct from traditional chemotherapy-related adverse effects. The irAEs caused by ICI therapy result from the infiltration of activated T cells into normal tissues. Various organ systems can potentially be affected by ICI treatment; nevertheless, previous ICI trials in HCC have shown these agents to be reasonably well tolerated. Nivolumab demonstrated an acceptable safety profile in Phase I/II and Phase III trials^[16,54]. Pembrolizumab has similar safety data^[27], as does durvalumab, which is the only anti-PD-L1 monoclonal antibody being studied in HCC, although only Phase I/II trial data is available^[55]. It has also been suggested that antitumor response can be enhanced using combinations of drugs with different molecular targets. Thirty-eight percent of HCC patients receiving combined nivolumab plus ipilimumab (anti-CTLA-4 antibody) therapy developed Grade 3/4 treatment-related adverse events. However, only 5% of patients required treatment discontinuation^[56]. ICI therapy is now also used in combination with vascular endothelial growth factor A. The recently FDA-approved regimen of atezolizumab plus bevacizumab induced grade 3/4 adverse events in 56% of treated patients, but very few patients required related discontinuation of treatment^[28].

Hepatotoxicity is one of the most concerning irAEs related to ICI use. The most common form of liver injury is hepatitis, which is characterized by a marked elevation in aminotransferases with or without an elevation in bilirubin levels. The onset of liver injury is typically within several weeks of therapy initiation. The severity of hepatitis is related to the degree of elevation in aminotransferase and bilirubin levels. The prevalence of hepatic injury related to ICI monotherapy use ranges from 2%-10% in various clinical trials^[57]. Significant liver toxicity (Grade 3/4) is rare. However, combination ICI therapy has been associated with higher rates of hepatotoxicity^[58], an observation that is likely related to anti-CTLA4 therapy, which reportedly has greater toxicity than PD-1 or PD-L1 inhibitors^[59]. Severe hepatotoxicity is typically treated with high dose corticosteroids, and the majority of patients respond well to this treatment^[60].

IMMUNOTHERAPY ADVERSE EVENTS IN POST TRANSPLANT PATIENTS

FUTURE DIRECTIONS

ICIs appear to demonstrate good anticancer efficacy in the transplant setting but pose a significant risk of graft rejection. The paucity of data generated from ICI use post-transplant - most of which are from individual cases - makes it hard to devise recommendations for their use in this setting. Controlled studies are needed to assess the efficacy and safety of these agents peri-transplant, during which the following should be explored: age of recipient; timing of ICI use in relation to LT; and the use of biomarkers (such as PD-1/PD-L1 expression in the graft) to predict ICI therapy. A sequential series of clinical trials might start with a prospective early phase study to evaluate neoadjuvant IO therapy pre-LT. Patients who have had a response to ICI therapy for HCC (i.e., in the setting of advanced HCC) may be evaluated for LT, and those who are candidates for LT may be enrolled for transplant in 6 or 12 months following the last dose of ICI. During this period, no further IO therapies is allowed, although bridging therapies (i.e., locoregional therapies) may be employed. This study would help determine a safe duration between IO and LT. Rates of graft rejection would be evaluated as the primary endpoint; secondary endpoints include PFS and OS. If this neoadjuvant approach is shown to be safe, further studies can be considered for post-transplant IO therapy. Once the appropriate patient characteristics are defined, a treatment algorithm may be generated to guide clinicians in the use of ICIs in the peri-transplant setting with the aim of providing effective IO to patients that can and should be allowed to benefit.