Role of liver microbiome and immune-related biomarkers in predicting response to immunotherapy in hepatocellular carcinoma.
Final Report Abstract
Liver cancer is the 6th most common cancer and the 3rd most common cause of cancer related death. Hepatocellular carcinoma (HCC) represents about 80% of primary liver cancer. About 50% of patients with HCC will eventually need systemic therapy. After one decade of Sorafenib as standard of care, a seminal trial showed superior results of the combination therapy of atezolizumab (atezo), an immune checkpoint inhibitor, and bevacizumab (bev), an anti-neo-vascular drug, when compared to Sorafenib, and establishing this treatment combination as new standard of care in advanced HCC cases. However, only about 30% respond to this treatment, underlying the need for biomarkers to identify the patients responding to this treatment combination. To do so, we investigated the tumor microenvironment, consisting of tumor cells, immune cells and stromal cells. Since immune checkpoint inhibitors aim to overcome the inhibition of T-cells through the tumor or its microenvironment, we focused primarily on immune cells in this project. We identified two distinct molecular subtypes associated with clinical benefit from atezo + bev in advanced HCC—termed “Immune-competent” and “Angiogenesis-driven”—and delineate key features of primary resistance to this therapy. These findings offer a molecular framework for patient stratification based on treatment response and inform potential strategies to overcome resistance. In a second study, we investigated the safety and efficacy of locoregional therapy (LRT) in combination with atezo + bev in terms of neo-adjuvant therapy for HCC before liver transplantation (LT), since concerns regarding graft safety and rejection have hindered its use in the neoadjuvant liver transplant setting. LRT with atezo + bev demonstrated favourable oncologic response in the pre-liver transplant setting, with a manageable safety profile and no severe post-transplant rejection or graft loss. These preliminary findings support the potential to use atezo + bev in a neoadjuvant setting in terms of bridging and downstaging and broaden transplant eligibility for patients with more advanced HCC.
Publications
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Neoadjuvant atezolizumab plus bevacizumab prior liver transplantation for hepatocellular carcinoma. JHEP Reports, 7(2), 101246.
Tabrizian, Parissa; Marino, Rebecca; Bhoori, Sherrie; Zeitlhoefler, Marcus; Mehta, Neil; Banz, Vanessa; Gruttadauria, Salvatore; Iavarone, Massimo; Mazzarelli, Chiara; Simonotti, Nicolò; Yao, Francis; Mazzaferro, Vincenzo & Llovet, Josep M.
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Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma. Journal of Hepatology, 82(6), 1036-1049.
Cappuyns, Sarah; Piqué-Gili, Marta; Esteban-Fabró, Roger; Philips, Gino; Balaseviciute, Ugne; Pinyol, Roser; Gris-Oliver, Albert; Vandecaveye, Vincent; Abril-Fornaguera, Jordi; Montironi, Carla; Bassaganyas, Laia; Peix, Judit; Zeitlhoefler, Marcus; Mesropian, Agavni; Huguet-Pradell, Júlia; Haber, Philipp K.; Figueiredo, Igor; Ioannou, Giorgio; Gonzalez-Kozlova, Edgar ... & Llovet, Josep M.
