Weighing Immunotherapy for Bridging and Downstaging Before HCC Transplant

Immune checkpoint inhibitors (ICIs) are increasingly used to bridge and downstage patients with hepatocellular carcinoma (HCC) who are awaiting liver transplant, raising questions about patient selection, rejection risk, and treatment timing.

At The Liver Meeting® 2026, CancerNetwork® spoke with Neil Mehta, MD, a transplant hepatologist, professor of medicine, and director of the Liver Cancer Multidisciplinary Program at the University of California, San Francisco (UCSF), and Laura Kulik, MD, professor of medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine, about integrating immunotherapy into transplant pathways for HCC.

Kulik and Mehta began by explaining how tumor burden and α-fetoprotein (AFP) levels guide the choice between locoregional therapy, immunotherapy, or both while patients wait for transplant. They then reviewed safety data from the multicenter VITALITY study and other cohorts, the case for a washout period of roughly 2 months before transplant, and evidence that immunotherapy can downstage patients beyond the Milan criteria. The pair also discussed how multidisciplinary teams coordinate treatment holds with organ offers, what transplant pharmacists and nurses should monitor after surgery, and the evidence still needed before immunotherapy becomes a more routine bridging strategy.

CancerNetwork: For patients with HCC awaiting liver transplant, how do you decide whether to bridge with locoregional therapy alone, immunotherapy alone, or a combination? Which patient or tumor features drive that choice?

Kulik: That is a big question. Most patients in the United States will undergo some form of bridging therapy because we have a 6-month waiting period. We do not want patients to drop out; we want the tumor to be controlled. If someone is within the Milan criteria, which is what we continue to use in the US — 1 lesion up to 5 cm, or 3 lesions, none greater than 3 cm — and has an AFP level less than 1000 [ng/mL], those are patients we would just bridge, and we generally would not consider immunotherapy.

If a patient has more advanced disease and needs to be downstaged or has features such as a high AFP or radiographic features, called radiomics, that suggest aggressive behavior, those are patients for whom we would consider a combination of immunotherapy plus locoregional therapy. If someone ultimately does not look like a transplant candidate because they have bilobar disease or significant tumor burden, transplant is not on the table. We would start with systemic therapy up front and then potentially consolidate with locoregional therapy if there is an area that is not responding.

Mehta: I agree. The only thing I would add is that when we have a patient with multifocal disease or a high AFP and we start with locoregional therapy, if there is a complete response, we are happy, and we monitor them. However, many of these patients will have a partial response and still have viable disease, or maybe their AFP comes down only from 250 to 200 [ng/mL]. Those are patients for whom we start to think about adding another type of therapy, including immunotherapy, vs the patients with a complete response, whom we just monitor.

Kulik: Our goal for transplant is to achieve a complete radiographic response that will hopefully translate into a complete pathologic response, because that has been shown to be associated with the best outcomes in terms of tumor recurrence.

Rejection is a key concern with ICIs before transplant. What have studies such as VITALITY shown about safety, and how long of a washout period do you recommend before surgery?

Mehta: VITALITY is a multicenter study of patients receiving immunotherapy for HCC before transplant. It was originally retrospective, but we are now collecting prospective data.¹ VITALITY and other studies have shown that immunotherapy appears safe to use. In terms of effectiveness, we think it is effective, but we will need more time and more prospective studies to confirm that.

If you take everyone who received immunotherapy, the rejection rate seems to be in the 15% to 20% range, but that depends on when the last dose of immunotherapy was given before transplant. Most studies now suggest that if you have at least 50 days from your last dose of immunotherapy to transplant, your rejection rate should be similar to that of patients who did not receive immunotherapy.² Many of us use that threshold of around 2 months to make sure patients are off therapy, if possible, before we move forward.

That is not always possible. If someone decompensates, their Model for End-Stage Liver Disease [MELD] score shoots up, and you have to move forward with transplant, we do not say, “You received immunotherapy 3 weeks ago, so we are not doing transplant.” It becomes a case-by-case discussion about the entire clinical picture and whether to move forward.

Kulik: Many of the guidelines and guidance statements support this. They have looked at the half-life, which is different for each immunotherapy. Most people land on 2 to 3 half-lives as a good starting point for the interval before moving forward with transplant. However, I agree; we have had patients who decompensate, and you do not have time to wait. It is an up-front discussion that you have to have with the patient and the team: if, by chance, this person has an aggressive rejection episode, would we move forward with a repeat transplant? That has been done in some instances and has shown good outcomes. You have to be up front with the patient about what happens if you get stuck in that situation.

Can immunotherapy, with or without locoregional therapy, safely downstage patients beyond the Milan criteria to transplant eligibility? How should teams confirm the response is durable enough to proceed?

Kulik: The answer is a definitive yes. Many of these studies have been retrospective, including the VITALITY study. The first prospective study was the XXL trial [NCT01387503] out of Italy.³ We have seen that some patients, but not all, can be downstaged. We would want more patients to respond, and the problem is that we cannot tell up front who will and will not respond, so we have to move forward and try.

The short answer is yes: we can get patients downstaged, even patients with minimal portal vein invasion. For patients who have main portal vein invasion or evidence of metastatic disease, we say no, we are not going to try. It is a multidisciplinary discussion about when to start and whether to start with locoregional or systemic therapy. The paradigm has shifted from “you should not do this before transplant” to “yes, this is another tool we can use to get patients to transplantation.”

Mehta: On the observation period, when you have a more standard downstaging patient, many of us think 3 months is a sufficient observation period to say that the patient seems okay to move forward with transplant. However, when the initial tumor biology is more aggressive, such as the patients with vascular invasion that Laura mentioned, we think we might need to observe them longer to make sure they will do well with transplant. Right now, for patients with tumor in vein [involving a portal vein branch], the tumor needs to be [stable] for 12 months before they can be considered for MELD exception points.⁴ The observation period varies depending on the initial tumor stage.

How should transplant hepatology, surgery, interventional radiology, and medical oncology teams coordinate the timing of immunotherapy, organ offers, and surgery, especially when a liver becomes available unexpectedly?

Kulik: The key is that you have had that discussion before the liver becomes available. Many of us have multidisciplinary teams, and some of us have everyone under the same roof seeing the patients. When we discuss patients after their scans, the oncologist is generally there. If we see a good response, we tell them we are going to move forward with starting the exception-point period, which is 6 months. Once the patient reaches the 3-month mark, we say, “We should stop [immunotherapy] because we have 3 months to go.” As soon as we get those exception points, we want to be able to move forward. The key is communication between the teams.

Mehta: I agree. Much of it also depends on expected wait times in your region. What I might tell a patient in San Francisco might be different from what Laura tells a patient in Chicago; it depends a lot on wait times and blood types. As long as you have a sense that, on average, this patient is going to wait about a year, you do the math and say, “Around the 9-month mark, we are going to start holding [immunotherapy] and get ready for transplant.” As Laura said, it is about up-front discussions with the important stakeholders, including the patients, so that no one is surprised at the end. If a liver becomes available unexpectedly, we are already ready for that.

What should transplant pharmacists and nurses watch for in patients who received immunotherapy before transplant, from immune-related adverse events to adjusting immunosuppression after surgery?

Kulik: Dr Mehta and I debated this last year at The Liver Meeting, and it is labor intensive. You have to watch those patients closely. In general, patients are at highest risk of rejection within the first 12 months after transplant, and if they have had immunotherapy, theoretically, they are at higher risk. Watching the liver enzymes, aspartate aminotransferase [AST] and alanine aminotransferase [ALT], is generally most important.

Then there is watching their immunosuppression. There will be discussions about adding therapy, such as mycophenolate mofetil [MMF], for that reason, as opposed to for renal sparing, which is what we usually use it for, and about whether to use induction therapy. If those numbers are going up, you want to do a biopsy sooner rather than later so that you can start to quiet down that liver and potentially get to the point where the liver is salvaged.

Mehta: That is important, because many studies show that rejection happens, but it does not necessarily lead to graft failure. As long as you are looking out for it, performing a biopsy, and treating it, most of these patients will recover. Having rejection because of immunotherapy before transplant does not mean graft failure is inevitable; that is uncommon.

What evidence do we still need before immunotherapy becomes a standard bridging strategy, and how should transplant centers track waitlist dropout, rejection, and recurrence to guide practice in the interim?

Mehta: I am not sure we will ever get to a place where immunotherapy is standard for all patients with HCC who are awaiting transplant. There are adverse effects, it is expensive, and many patients do not need it. If you have a patient with a single HCC that is, say, 2.5 or 3 cm, and you perform a radiation segmentectomy with yttrium-90 [Y-90], by and large, that patient will have an excellent response, a high chance of making it to transplant, and a low risk of waitlist dropout.

Our goal is to understand who benefits from additional immunotherapy during the waiting period. As Laura mentioned earlier, those are patients with higher-risk features: a higher AFP, multifocal disease requiring downstaging, or perhaps portal venous invasion. We have to identify the higher-risk cohorts that face a high risk of waitlist dropout unless we add immunotherapy. That is where the field has moved, to try to improve intention-to-treat survival for those patients, because a whole group of patients will probably make it to transplant without immunotherapy.

Kulik: That is a good point, because it brings up the studies we have had thus far of transarterial chemoembolization [TACE] plus immunotherapy, which did not build in patients going to transplant. Future studies have taken this into account. We are waiting on several Y-90 plus immunotherapy studies. Two are single arm, and 1 is randomized, so we will get more data from that. We will see which patients go on to be listed, who makes it to transplant, who drops out, and so on.

In terms of whether it will ever become standard of care, I do not think we will necessarily see it as standard of care in guidelines or guidance, but I do think it will become more of a center-level standard of care, and that may be different for each center.

References

1. Tabrizian P, Holzner ML, Ajmera V, et al. Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study. J Hepatol. 2025;82(3):512-522. doi:10.1016/j.jhep.2024.09.003
2. Moeckli B, Wassmer CH, El Hajji S, et al. Determining safe washout period for immune checkpoint inhibitors prior to liver transplantation: an international retrospective cohort study. Hepatology. 2025;82(5):1122-1137. doi:10.1097/HEP.0000000000001289
3. Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020;21(7):947-956. doi:10.1016/S1470-2045(20)30224-2
4. OPTN Liver and Intestinal Organ Transplantation Committee. Guidance to liver transplant programs and the National Liver Review Board for: adult MELD exceptions for transplant oncology. Organ Procurement and Transplantation Network. December 4, 2025. Accessed November 6, 2026. https://tinyurl.com/4s92xrbs