Targeting Tumor Microenvironment in Liver Cancers: Rationale, Current Progress, and Future Perspective

Abstract

Surgical treatments offer the chance for cure in primary or metastatic liver cancers. However, many patients experience disease progression after surgical interventions, or cannot undergo surgery as they present with unresectable disease at diagnosis. In such cases, available treatment options (local and systemic) have been limited in efficacy, which led to dismal survival rates in advanced hepatocellular carcinoma (HCC), intrahepatic colangiocarcinoma (ICC) or metastatic pancreatic ductal adenocarcinoma (PDAC). More recent developments in oncology have offered renewed hope for advanced liver cancer patients. Hypofractionated radiation has shown feasibility and promise in unresectable setting, and is now being tested in a randomized phase III trial in HCC (clinicaltrials.gov identifier NCT03186898). Antiangiogenic agents have strongly impacted the management of advanced HCC, with multiple drug options in first line setting (sorafenib, lenvatinib) and second line setting (regorafenib, cabozantinib, ramucirumab). Chemotherapy based regimens are standard of care in ICC and PDAC. Immunotherapy with anti-PD-1/PD-L1 or anti-CTLA4 antibodies has shown real potential to transform advanced HCC therapy, both in first line and second line settings. Finally, combinations of these new strategies are very attractive approaches, as they promise durable and profound responses in advanced HCC. But in order to achieve this promise more broadly, these concepts require greater understanding based on mechanistic preclinical studies and validation in correlative studies in clinical trials as a basis to establish optimal combinatorial strategies. The insights gained from this "bench to the bedside and back" approach raise the hope for a more efficient development of targeted agents in combination, and in earlier stages of the disease, with the goal of increasing survival in patients afflicted with this aggressive and deadly diseases. (Presented at the 2001st Meeting, July 4, 2022).