Downstaging of advanced hepatocellular carcinoma followed by liver transplantation using immune checkpoint inhibitors: Where do we stand?

Table 1 Studies analysed and their key findings

Ref.	Design	Sample size	ICIs used	Key findings
Tabrizian et al[11]	Case series	9	Nivolumab	Significant PD-L1 expression in donor allograft may indicate a subclinical all-immune response and identify patients at high risk of rejection
Chen et al[12]	Case report	1	Toripalimab	The effect of PD-1 antibody leads to the failure of the graft’s attempt to achieve “immune escape” by expressing PD-L1, which results in fatal acute rejection response
Nordness et al[13]	Case report	1	Nivolumab	Profound caution is needed when using nivolumab in patients with HCC who are either still awaiting or have previously undergone solid organ transplant. It is unclear given their mechanism of action, if a defined waiting period would be helpful before transplant
Kumar et al[14]	Case report	1	Atezolizumab, Bevacizumab	Atezolizumab plus bevacizumab effective as downstaging therapy for liver transplantation in HCC with PVTT
Aby et al[15]	Case report	1	Nivolumab	In carefully selected patients, ICI may serve as a bridge to LT
Chouik et al [16]	Case report	1	Atezolizumab + Bevacizumab	Complete clinical remission achieved; successful LT with no recurrence at 10-month follow-up
Kuo et al[17]	Case series	4	Atezolizumab, Nivolumab, Pembrolizumab	Safe washout period of 42 days recommended for LT following ICI therapy
Schnickel et al[18]	Case Series	5	Nivolumab	Pretransplant use of ICIs, particularly within 90 days of LT, was associated with biopsy-proven acute cellular rejection and immune-mediated hepaticnecrosis

ICI: Immune checkpoint inhibitors; PD-L1: Programmed death ligand 1; HCC: Hepatocellular carcinoma; PVTT: Portal vein tumor thrombosis; LT: Liver transplantation.

Table 2 Recommendations

Aspect	Recommendation
Indications	HCC: Patients requiring downstaging therapy before liver transplantation. PVTT: Patients with HCC complicated by PVTT who are candidates for liver transplantation
Contraindications	Autoimmune diseases: History of severe autoimmune diseases that could be exacerbated by ICIs. Infections: Ongoing significant infections that may be worsened by immunotherapy. Liver disease: Decompensated liver disease where the risks of ICIs outweigh potential benefits
Timing of ICI initiation	Pre-transplant downstaging: Start ICIs as part of a structured downstaging protocol for HCC to shrink tumors to within transplant criteria. Advanced HCC management: Initiate ICIs in patients with advanced HCC and PVTT to control disease progression pre-transplant
Timing of ICI cessation	Before liver transplantation: Stop ICIs at least 4-6 weeks prior to planned liver transplantation to reduce the risk of graft rejection. Immune resolution: Ensure resolution of immune activation and monitoring for potential adverse effects post-ICI cessation before proceeding to LT
Monitoring and follow-up	Regular assessment: Frequent monitoring of liver function and immune response during ICI treatment. Post-ICI cessation: Close follow-up after stopping ICIs to detect and manage any late-onset immune-related adverse events and ensure patient readiness for transplantation
Immunosuppressive strategy post-LT	Standardized protocols: Implement standardized immunosuppressive regimens tailored to the patient's condition and prior ICI therapy to prevent graft rejection. Adaptive management: Adjust immunosuppression based on patient response and any emerging complications post-transplant

ICI: Immune checkpoint inhibitors; HCC: Hepatocellular carcinoma; PVTT: Portal vein tumor thrombosis; LT: Liver transplantation.