Immunotherapy Before HCC Transplant: Balancing Downstaging Gains Against Rejection Risk and Timing

At The Liver Meeting 2026, two transplant specialists sat down with CancerNetwork to work through a question that has moved quickly from taboo to practice: should patients with hepatocellular carcinoma (HCC) who are waiting for a new liver receive immune checkpoint inhibitors first? Neil Mehta, MD, a transplant hepatologist and director of the Liver Cancer Multidisciplinary Program at UCSF, and Laura Kulik, MD, of Northwestern Medicine, said the paradigm has shifted from "you should not do this before transplant" to treating immunotherapy as one more tool for getting patients to surgery.

The starting point is the wait itself. In the United States, Kulik explained, most patients undergo some form of bridging therapy because of a 6-month waiting period, and the aim is to keep the tumor controlled so patients do not drop off the list. Patients within Milan criteria (one lesion up to 5 cm, or three lesions none larger than 3 cm) with an AFP below 1000 ng/mL are generally just bridged with locoregional therapy, without immunotherapy. Those needing downstaging, or showing a high AFP or radiographic features suggesting aggressive behavior, are candidates for immunotherapy combined with locoregional treatment. Patients with bilobar disease or heavy tumor burden are not transplant candidates at the outset; they start with systemic therapy, with locoregional therapy added for any area not responding.

Mehta added that response to first-line locoregional therapy often decides the next step. A complete response means monitoring. Many patients with multifocal disease or high AFP get only a partial response, with viable tumor remaining, or an AFP that falls only from 250 to 200 ng/mL. Those patients prompt consideration of added therapy. The goal, Kulik said, is a complete radiographic response that translates into a complete pathologic response, which has been tied to the lowest recurrence rates.

Rejection is the central worry. Mehta described the multicenter VITALITY study, originally retrospective and now gathering prospective data, which along with other work suggests immunotherapy appears safe. Effectiveness, he said, looks promising but needs more prospective confirmation. Across everyone treated, rejection runs about 15% to 20%, but timing matters: studies suggest that with at least 50 days between the last dose and transplant, rejection rates resemble those of patients who never received immunotherapy. Many centers use roughly 2 months as the threshold. Kulik noted that guidance statements often use 2 to 3 half-lives of the specific drug.

That window cannot always be honored. If a patient decompensates and their MELD score surges, Mehta said, teams do not refuse transplant because the last dose was three weeks earlier; it becomes a case-by-case decision. Kulik said teams should discuss up front whether a repeat transplant would be pursued if aggressive rejection occurred. That has been done in some instances with good outcomes.

On downstaging beyond Milan, Kulik's answer was a definitive yes, with caveats. Many studies are retrospective, including VITALITY; the first prospective study was the XXL trial (NCT01387503) from Italy. Some patients, but not all, are downstaged, and there is no way to predict responders in advance. Even minimal portal vein invasion can be downstaged, but main portal vein invasion or metastatic disease rules out the attempt. Mehta said about 3 months of observation is generally enough for standard downstaging patients, while those with vascular invasion need longer. Currently, tumor in a portal vein branch must be stable for 12 months before MELD exception points can be considered.

Coordination, both said, must be settled before a liver appears. Kulik described teams, sometimes under one roof, that review scans with the oncologist present. After a good response, the 6-month exception-point period begins, and at the 3-month mark immunotherapy is stopped. Mehta said the plan depends on regional wait times and blood types: if the expected wait is about a year, holding therapy might start around month 9.

After surgery, monitoring is labor intensive. Rejection risk is highest in the first 12 months. Kulik pointed to AST and ALT as the key measures, and to discussions about adding mycophenolate mofetil for rejection prevention rather than kidney sparing, and about induction therapy. Rising numbers call for early biopsy. Mehta stressed that rejection does not usually mean graft failure; with biopsy and treatment, most patients recover.

Mehta doubts immunotherapy will become standard for all waitlisted HCC patients, citing adverse effects, expense, and the many who do not need it. A single 2.5 or 3 cm tumor treated with Y-90 radiation segmentectomy usually does well. The task is identifying higher-risk groups, such as those with high AFP, multifocal disease, or portal vein invasion. Kulik noted earlier TACE-plus-immunotherapy studies did not build in transplant, and that several Y-90-plus-immunotherapy studies, two single-arm and one randomized, are awaited.