Immunotherapy Before and After Liver Transplantation
Summary of CME Lecture by Kymberly Watt, MD
1. Main Clinical Topics Discussed
- Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) — both pre- and post-liver transplantation
- Downstaging strategies using ICIs to achieve transplant eligibility
- Peri-transplant timing of ICI therapy and rejection risk
- Long-term post-transplant outcomes with emphasis on malignancy as a leading cause of death
2. Key Learning Points, Guidelines, and Recommendations
Pre-Transplant ICI Use:
- ICIs (immune checkpoint inhibitors) are now the standard of care for advanced HCC, with the atezolizumab + bevacizumab combination (IMbrave150) established as first-line therapy
- ICIs were historically reserved for non-transplant candidates but are increasingly being considered for downstaging to transplant eligibility
- ICI use typically follows failure of local-regional therapy and/or tyrosine kinase inhibitors (TKIs)
- Combination therapy (dual checkpoint inhibition ± TKI) increases adverse events, including autoimmune-like hepatitis
- PD-L1 is expressed on hepatocytes, cholangiocytes, Kupffer cells, and endothelial cells; PD-1 staining is more prominent adjacent to the HCC tumor itself
- Disease etiology influences ICI response and toxicity:
- PD-L1 expression is higher in viral hepatitis (HBV)
- PD-1 expression is higher in autoimmune liver disease
- Patients with NAFLD/NASH may have a significantly diminished response to ICI therapy (preliminary data; small sample sizes)
- Viral reactivation does not appear to be significantly increased with ICI use (reassuring but limited data)
Peri-Transplant Timing — Critical Recommendation:
- All ICIs have long half-lives of approximately 3–4 weeks (15–27 days); CTLA-4 inhibitors are slightly shorter
- Based on a systematic review of 24 studies (n = 45 transplant patients), rejection risk is directly correlated with proximity to last ICI dose:
- < 1 half-life from last dose: ~80% rejection rate
- 1–3 half-lives: ~30% rejection rate
- 3–5 half-lives: ~10–15% rejection rate
- Recommendation: Delay transplantation as far from last ICI dose as possible; living donor transplant planning should leverage timing flexibility
- Interventions to consider when transplant cannot be delayed:
- IVIG, plasmapheresis, or plasma exchange
- Induction immunosuppression (e.g., ATG, IL-2 receptor inhibitors)
Post-Transplant Malignancy:
- Malignancy is a leading cause of long-term death after liver transplantation
- Younger transplant recipients carry the highest *incremental* cancer risk — they are expected to have low cancer rates but demonstrate cancer rates equivalent to older transplant populations
- Standard population-based cancer screening protocols underestimate risk in immunosuppressed transplant recipients and need reconsideration
3. Specific Clinical Data and Study Results Cited
- Chinese cohort study (n = 100): Unresectable advanced HCC treated with TKI + PD-1 inhibitor:
- 10% complete response; 40% partial response; 30% stable disease; 15% progression
- 24 patients underwent surgical resection following response
- 10/24 achieved complete pathologic response post-resection
- 5/10 complete responders experienced post-resection liver failure/complications
- >90% one-year survival and ~75% two-year survival in the resected group
- Systematic review (24 studies, n = 45 transplant recipients post-ICI):
- 24 experienced rejection; 2 antibody-mediated rejection
- 4 graft losses; 4 rejections resolved
- 3 early