Breakthrough study defines ideal interval for immunotherapy and liver transplants

Hepatocellular carcinoma (HCC) represents about 80 to 90% of cases of primary liver cancer. On a global level, 905,700 new cases and 830,200 deaths were registered in 2020 according to the World Health Organization. In Switzerland the Statistics Office lists 960 new cases and 720 deaths every year. HCC is the third cause of death due to cancer in the world and fifth in Switzerland.

Immunotherapy and liver transplantation

Amongst available treatments for HCC, liver transplantation stands as the most definitive treatment, offering select patients the possibility of long-term remission or even a complete cure. More recently, immunotherapy through immune checkpoint inhibitors (ICI) which stimulate the immune system of patients to attack cancerous cells has emerged with very promising results: a positive response in one third of cases and even a complete disappearance of tumors in some patients. Given this effectiveness, ICI treatments are being gradually recognized as the first line of treatment for advanced HCC.

Combining treatments

Currently the response of ICI is not sustainable because cessation of treatment could provoke recurrence of the cancer.

To address this, the idea is to combine immunotherapy and a transplant, in other words offering patients who have responded to ICI treatment a new liver, with the potential to eliminate both their cancer and underlying liver disease."

Beat Moeckli, Senior Resident of Abdominal Surgery at the HUG and Postdoctoral Researcher at the Department of Surgery in the Faculty of Medicine at the UNIGE, first author of the study

Unfortunately, use of ICI exposes patients to an increased risk of a rapid rejection of the graft. "Immunotherapy stimulates the immune system so that it recognizes tumors as foreign bodies. In the case of a transplant, immune cells stimulated in this way will also potentially attack the graft with more effectiveness. We must therefore stop ICI treatment before the transplant in order to reduce this risk," he continued.

Therefore, to reconcile the two approaches, it is essential to determine the optimal treatment window, namely the interval between ceasing the ICI treatment and the liver transplant. To identify this, an international team led by the HUG and the UNIGE, conducted a retrospective study involving 29 leading hospitals in Europe, Asia and the USA. In total, data from 119 patients suffering from HCC who had received immunotherapy treatment before a liver transplant were analyzed by the Geneva team in order to evaluate the rejection incidence of the transplant, the loss of the graft and recurrence post-transplantation.

An optimal interval

The results indicate that the shorter the interval between the last ICI treatment and the graft, the higher the rejection risk. An interval less than 30 days multiplies the rejection risk by 21.3. Between 30 and 50 days the risk is only increased by 9.5. In contrast, an interval longer than 50 days translates into a rejection rate that is significantly lower. "Our work shows that 50 days constitute the optimal interval." Below this, the rejection risk is too high, and above it the disease may progress," specifies Christian Toso, Head of the Division of Abdominal Surgery at the HUG, Full Professor at UNIGE and last author of the study.

A breakthrough for liver transplants

Thanks to the foundational work carried out by Christian Toso, the HUG are playing a key role in the optimization of eligibility criteria for liver transplantation for patients suffering from HCC. In fact, his research has contributed to define models that integrate biomarkers and total tumor volume to optimize patient selection and reduce the risk of recidivism. Building on this, the new study will support the integration of immunotherapy into the treatment pathway for transplant candidates and position the HUG as a global center of excellence in this field.

This research represents a significant step towards developing official recommendations for liver transplantation in patients receiving immunotherapy. "These guidelines will be essential and are expected to be established soon. Our study will hopefully play a key role in expanding access to transplants and therefore improve remission rates," concludes Beat Moeckli.

¹ Primary relates to the organ or anatomical site where the tumor progression began.