Approach to immunotherapy for HCC in the liver transplant population

INTRODUCTION The success of immunotherapy for advanced stages of HCC has sparked interest in their broader utility within the field. As HCC remains one of the most common indications for liver transplant consideration, the safety and efficacy of immunotherapy in this context warrants clarification. Immunotherapy before or after organ transplantation has been historically discouraged, largely stemming from concerns of precipitating allograft rejection. Notwithstanding such concerns, the potent ability of immunotherapeutics to control HCC has facilitated cautious exploration of their use as both bridging and downstaging treatment modalities before transplantation. A similar rationale has led to their off-label use for both recurrent HCC and non-liver–related malignancies in the posttransplant setting. This review highlights the field’s current understanding of immunotherapy in the context of liver transplantation, underlining necessary areas of future investigation. BACKGROUND While single-agent immunotherapy has modest benefits for HCC, a combination approach has proven most efficacious. The IMbrave150 trial was the first to demonstrate a significant survival benefit with the combination of atezolizumab (anti-programmed cell death ligand-1 [PD-L1] antibody) and bevacizumab (anti-VEGF inhibitor antibody), where atezolizumab-bevacizumab combination increased median overall survival to 19.2 months in comparison with 13.4 months with sorafenib monotherapy.1 The HIMALAYA trial showed positive results with a different combination of immune checkpoint inhibitors, durvalumab and tremelimumab, which respectively target PD-L1 and cytotoxic T-lymphocyte–associated protein 4.2 In the HIMALAYA trial, a single infusion of tremelimumab followed by regular intervals of durvalumab infusions led to a median overall survival of 16.4 months versus 13.8 months with only sorafenib. These trials led to the approval of both regimens as first-line therapies for unresectable advanced HCC. Mounting evidence also suggests a role for immunotherapy in both neoadjuvant and adjuvant settings (Figure 1). Novel data showed clinical benefit with atezolizumab and bevacizumab as adjuvant therapy after curative interventions (eg, surgical resection or percutaneous ablation) for HCC tumors with high-risk features.3 The IMbrave050 trial was the first phase III study to show the utility of adjuvant immunotherapy in those with high-risk HCC tumors, demonstrating a significant improvement in recurrence-free survival with atezolizumab and bevacizumab in comparison with active surveillance (HR 0.72 with p-value 0.012).4 As such, the use of adjuvant immunotherapy in this setting was incorporated into the latest guidance statement from the American Association for the Study of Liver Diseases.5 Further support for immunotherapy as an adjunctive option was shown in recent findings from the phase III trial, EMERALD-1, that were recently presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium. EMERALD-1 showed a synergistic role of adjuvant durvalumab and bevacizumab after transarterial chemoembolization, as this combination of therapies improved progression-free survival in comparison to transarterial chemoembolization monotherapy (15 mo vs. 8.2 mo).6 Taken together, immunotherapies have increasingly established their role across the HCC treatment landscape and appear positioned to further expand their therapeutic footprint (Figure 2).FIGURE 1: Mechanistic rationale for neoadjuvant and adjuvant immunotherapy in HCC treatment. In A, the immunomodulatory effects of the 3 major classes of immunotherapies utilized for HCC treatment are summarized. Immune checkpoint inhibitors include anti-PD-1 (eg, nivolumab, pembrolizumab), anti-PDL-1 (eg, atezolizumab, durvalumab), and anti-CTLA-4 agents. (eg, ipilimumab). Antibodies designed to inhibit immune checkpoint receptor-ligand interactions (eg PD-1/PDL-1 and CTLA-4/CD80) restore T cell activation within the tumor microenvironment, enhancing immune-mediated anti-tumor responses. VEGF inhibitors (eg, bevacizumab) affect angiogenesis within the tumor microenvironment, leading to relative tumor hypoxia (vessel pruning) and may also improve drug delivery and mobilization of immune cells by normalization of the tumoral vasculature. In B, the rationale for immunotherapy as adjuvant or neoadjuvant therapy is graphically depicted. Immunotherapy before surgery or LRT (termed neoadjuvant use) augments immune-mediated anti-tumor response, potentially reducing tumor burden and treating microscopic (eg, nonvisible) disease. This could improve outcomes of definitive therapeutic interventions by reducing the size of the tumor before resection or ablation and may ultimately reduce rates of postoperative tumor recurrence. A concern with neoadjuvant therapy is that it may delay the time to definitive therapeutic interventions. Immunotherapy after curative interventions (term adjuvant use) has demonstrated clinical benefit in reducing HCC recurrence in cases of tumors with high-risk features. Surgical resection or LRT induces cell necrosis and release of tumor antigens, which is thought to favorably alter the tumor microenvironment and enhance the immune-mediated effects of immunotherapy. Abbreviations: Anti-CTLA-4, anti-cytotoxic T lymphocyte–associated protein-4; Anti-PDL-1, anti-programmed cell death ligand-1; APC, antigen-presenting cell; CTLA-4 (cytotoxic T lymphocyte-associated protein-4); DC, dendritic cell; LRT, locoregional therapy; PD-1, programmed cell death-1; PDL-1, programmed cell death ligand-1; TAM, tumor-associated macrophage; TME, tumor microenvironment.FIGURE 2: Evolving treatment paradigm for HCC. This figure summarizes the general treatment approach to HCC based on the stage of disease, highlighting expanding indications for immunotherapy across all stages of disease. Novel indications for immunotherapy with established efficacy are outlined in the figure, including use of adjuvant atezolizumab and bevacizumab after treatment of early-stage tumors with high-risk features (IMBravo050 trial), adjuvant durvalumab and bevacizumab after TACE for unresectable tumors (EMERALD-1 trial), and first-line use of either atezolizumab and bevacizumab or durvalumab and tremelimumab for unresectable advanced stages of HCC (IMBrave150 and HIMALAYA trials, respectively). Though standalone regimens with locoregional therapy are the current standard approach to bridging or downstaging therapy before liver transplantation (gray dotted arrow), there may be a role for immunotherapeutic regimens as bridging or downstaging treatments before liver transplantation for both intermediate and advanced stages of HCC (orange dotted lines). Treatment of recurrent HCC or de novo nonhepatic malignancies in the posttransplant setting with immunotherapies is also a viable area. Liver image licensed through iStock Getty Images (stock file ID: 1295846316). Abbreviations: BCLC, Barcelona Clinic Liver Cancer; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TKIs, tyrosine kinase inhibitors.IMMUNOTHERAPY BEFORE LIVER TRANSPLANTATION The efficacy of immunotherapy to control HCC underscores its value in those being considered for—or awaiting—liver transplantation. While liver transplantation offers a potentially curative option for those with HCC, around 30% of patients will dropout from the waiting list.7 Multiple factors contribute to the high dropout rate, including the 6-month wait period before exception point accrual, variable wait times due to organ shortages, and invariable progression of disease or death.7 These statistics highlight the frequent necessity to initiate HCC-targeted treatment before transplantation. This includes downstaging therapy to reduce tumor burden to meet qualifications for transplantation (Milan criteria) and bridging therapy to treat tumors while awaiting organ allocation.5 Locoregional therapy encompasses both transarterial and ablative therapies and is the primary tool for downstaging and bridging therapy. Immunotherapy has gained traction as an alternative or complementary approach in these settings. Small studies have employed immunotherapy as monotherapy, in combination with other immunotherapeutics or systemic agents, and as a (neo)adjunct option to resection, ablation, or transarterial treatments in the context of bridging or downstaging treatment regimens.8 Clinical responses within these contexts have been encouraging. In the neoadjuvant setting, pathological response rates of 20% have been observed in small trials, and case reports have shown atezolizumab and bevacizumab led to downstaging of significant tumor burden before transplantation.9,10 Clinical trials are underway to distill the role of immunotherapy before liver transplantation (Table 1). TABLE 1 - Current clinical trials on neoadjuvant immunotherapy for HCC before liver transplantation Trial ID Trial name Neoadjuvant HCC therapies before transplantation Study design (n) Primary end point Secondary end points Anticipated completion date NCT05411926 — PD-1 or PDL-1 monotherapy Prospective, observational, case-control (n = 60) Incidence and severity of allograft rejection OS, RFS, cellular immune function after transplantation, dose and drug concentration of tacrolimus after transplantation September 2023 NCT04425226 PLENTY 202001 Pembrolizumab with Lenvatinib Randomized, open-label (n = 192) RFS AE, DCR, and ORR December 2024 NCT04443322 DULECT 2020-1 Durvalumab with Lenvatinib Single arm, open-label (n = 20) RFS and PFS AE, ORR, and OS December 2025 NCT05185505 --- Atezolizumab with Bevacizumab Single arm, open-label (n = 24) Acute allograft rejection rate AE, ORR, OS, immune biomarkers, and proportion of patients who are removed from the transplant waitlist, receive a liver transplant, and whose liver explants have necrotic tumors October 2027 NCT05475613 --- Anti-PD-1 (pembrolizumab, nivolumab, or tislelizumab) with locoregional therapy Single arm, nonrandomized, open-label (n = 59) Event-free survival rate OS, rate of early allograft dysfunction, rate of allograft rejection, rate of successful tumor downstaging August 2028 NCT05027425 ESR-20-21010 Durvalumab with Tremelimumab Single arm, open-label (n = 30) Acute allograft rejection rate AE, OS, RFS, radiologic tumor response by RECIST or mRECIST, and pathologic response through liver explant assessment December 2030 Abbreviations: AE, adverse events; Anti-PD-1, anti-programmed cell death-1; DCR, disease control rate; mRECIST, modified response evaluation criteria in solid tumors; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumors; RFS, recurrence-free survival. SAFETY OF IMMUNOTHERAPIES The main concern with immunotherapy in the peri-transplant setting is allograft rejection (Figure 3). This was highlighted by a case report of immune checkpoint inhibitor use (nivolumab, a programmed cell death-1 inhibitor) in the pretransplant setting, which resulted in fatal hepatic necrosis in the immediate postoperative period from a severe immune checkpoint inhibitor-related immune reaction.11 Subsequent case studies have signaled more favorable safety outcomes. A recent meta-analysis of 45 patients receiving different immunotherapeutic regimens for HCC in the pretransplant setting found that 24% of cases incurred allograft rejection.8 In turn, the National Liver Review Board, a governing committee that develops national policies for organ transplantation, indicated that immunotherapy in the pretransplant setting does not disqualify liver transplant candidates from accruing HCC exception points.12 Nevertheless, interpretation of current data is limited by small sample sizes with multiple uncontrolled variables (eg, variability in immunotherapeutic and immunosuppressive regimens, absent liver biopsies to confirm allograft rejection). Clarity is needed to determine the safety implications of immunotherapy in the pretransplant setting, which is the expressed purpose of multiple active clinical trials (Table 1).FIGURE 3: Rationale and risk of immunotherapy peri-liver transplantation. Immunotherapy for HCC before liver transplantation is used as downstaging or bridging therapy. Its use in the posttransplant setting includes treatment of recurrent HCC or de novo nonhepatic malignancy. In either circumstance, immunotherapy pretransplantation or posttransplantation poses a risk of allograft liver rejection. Expression of immune checkpoint inhibitor ligands (eg, PDL-1) may potentiate the risk of allograft rejection. Abbreviations: anti-PD-1, anti-programmed cell death-1; anti-PDL-1, anti-programmed cell death ligand-1.The risk of immunotherapy-related allograft rejection may be partially modifiable, as early data indicate that the interval between the last infusion and the time of transplantation may influence allograft outcomes. Among three different case series, the risk of rejection was 75%, 12.5%, and 0% when the time interval between nivolumab infusion and transplantation was respectively within 16 days, 28 days, or greater than 90 days.8,13,14 Whether these pharmacokinetic observations apply to dual-agent regimens (eg, atezolizumab with bevacizumab) remain to be determined. Based on limited data and the known half-lives of immunotherapeutic agents (Table 2), expert opinion currently advises a minimum 12-week washout period from the last infusion before transplantation.5 TABLE 2 - Half-lives of immunotherapy agents used for HCC Immunotherapy agent Trade name Mechanism of action Estimated half-life (d) Atezolizumab Tecentriq PDL-1 inhibitor 27 Durvalumab Imfinzi PDL-1 inhibitor 18 Bevacizumab Avastin VEGF inhibitor 20 Nivolumab Opdivo PD-1 inhibitor 26.7 Pembrolizumab Keytruda PD-1 inhibitor 23 Ipilimumab Yervoy CTLA-4 inhibitor 15.4 Notes: Half-lives based on population pharmacokinetic analyses performed by the FDA.Source information collated from Woo SM, et al.7.Abbreviations: CTLA-4, cytotoxic T-lymphocyte–associated protein 4; FDA, Federal Drug Administration; PD-1, programmed cell death-1; PDL-1, programmed cell death ligand-1. USE OF IMMUNOTHERAPY IN THE POSTTRANSPLANT SETTING The role of immunotherapy in the posttransplant setting is not well studied, though treatment indications are evident. HCC recurs in 6%–18% of patients who originally underwent transplantation for HCC. De novo nonhepatic malignancies are also common, including cancers in which first-line therapy is immunotherapy, such as malignant melanoma, advanced stages of small cell lung cancer, and metastatic nonsmall cell carcinoma.15 Notwithstanding the potential role of immunotherapy for either recurrent HCC or nonhepatic malignancies, the risks posed to the liver allograft are of legitimate concern. In a recent systematic review and pooled analysis of case reports and series (n = 52), allograft rejection occurred in about 28% of liver transplant patients who received immunotherapy for either allograft HCC or de novo nonhepatic cancers.16 Predicting the risk of rejection in this setting is poorly understood. Some data indicate that immunological tolerance develops over time, conferring allograft protection from immune-mediated effects secondary to immunotherapy exposure. This was observed in prior case series, where graft rejection more frequently occurred in those with a shorter time interval between liver transplantation and immunotherapy exposure in the posttransplant setting.17 Whether allograft staining for immune checkpoint markers (eg, PD-L1) is predictive of rejection after immunotherapy remains another important area of investigation, as observations suggest a higher frequency of rejection in allografts with positive PD-L1 staining.18 CONCLUSION Immunotherapy in the liver transplant patient is a burgeoning frontier in the HCC treatment landscape. The efficacy of novel immunotherapeutic combinations and their promising use in adjuvant and neoadjuvant settings underline their potential impact at all stages of the disease. Favorable outcomes from small studies suggest a potential benefit in controlling tumor burden before liver transplantation. Their use has also been investigated for the treatment of recurrent HCC or certain de novo nonhepatic malignancies in the posttransplant setting. In both contexts, immunotherapy carries a heightened risk of allograft rejection, though early evidence indicates that a therapeutic washout time before liver transplantation may reduce the incidence of such immune-mediated complications and should not be considered a contraindication to transplant. Ongoing clinical trials seek to define their role in these settings, and we eagerly await the outcomes to clarify appropriate safety profiles. Until then, their use before or after liver transplantation must be carefully weighed against their risks of injury to the liver allograft.