Nivolumab plus ipilimumab for potentially resectable hepatocellular carcinoma: Long-term efficacy and biomarker exploration

Abstract

Background & aims: Immune checkpoint inhibitor-based combination therapy has demonstrated high objective response rates in patients with hepatocellular carcinoma (HCC) and may improve clinical outcomes as neoadjuvant or perioperative therapy. This study evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with potentially resectable HCC and explored predictive biomarkers of treatment response.

Methods: Eligible patients received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks. Tumor response was assessed after two and four treatment cycles. Patients then proceeded to curative surgery or alternative treatments according to clinical guidelines. Serial tumor and peripheral blood samples were collected for genomic and transcriptomic analyses and immune cell profiling.

Results: Among the 43 enrolled patients (men/women: 37/6; viral/non-viral: 41/2; Barcelona Clinic Liver Cancer stage A/B/C: 4/13/26; median tumor size: 8.7 cm), 24 underwent surgery, and eight achieved a major pathological response (>90% tumor necrosis). The estimated 4-year progression-free survival and overall survival rates were 44% (95% CI 28-59%) and 60% (95% CI 42-74%), respectively. Increased interferon-γ and tertiary lymphoid structure (TLS) signatures in resected tumors were associated with objective response. In a mouse liver cancer model, B-cell depletion abolished the efficacy of anti-programmed death-1 plus anti-cytotoxic T lymphocyte-associated protein 4 therapy, supporting the mechanistic role of TLS. Peripheral blood T-cell activation and exhaustion at baseline and post-immunotherapy, assessed using spectral flow cytometry and deep learning algorithms, correlated with response and survival.

Conclusions: Neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may improve long-term survival in patients with potentially resectable HCC. Immunotherapy-induced TLS formation is associated with enhanced antitumor immunity.

Impact and implications: Immune checkpoint inhibitor-based systemic therapy is now an integral component of the multidisciplinary management of patients with hepatocellular carcinoma. Findings from this single-arm clinical trial indicate that: i) neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may improve long-term survival in patients with potentially resectable hepatocellular carcinoma; ii) immunotherapy-induced tertiary lymphoid structure formation is associated with enhanced antitumor immunity; iii) monitoring T-cell exhaustion in peripheral blood may aid in the prediction of response to immunotherapy.

Clinical trial number: NCT03510871.

Keywords: T cell exhaustion; dendritic cells; neoadjuvant; peripheral blood mononuclear cells; tertiary lymphoid structure.