The 7th Joint Session between JDDW-KDDW-TDDW4(JDDW)
Thu. November 2nd   14:00 - 17:00   Room 10: Portopia Hotel Waraku
JKT4-RS1
 Importance of preclinical rationales to establish appropriate treatment sequences in the era of chemo-diversity for HCC
Hideki Iwamoto1, Hironori Koga1, Takumi Kawaguchi1
1Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine
Introduction
Nowadays, we have multiple lines of systemic therapy for hepatocellular carcinoma (HCC). We also have multiple conventional locoregional treatments. In the era of chemo-diversity, we face a new unmet medical need of difficulty in tailoring appropriate treatment sequences. In this point of view, the balance between preclinical rationale and clinical relevance is important to find appropriate treatment sequences. The purpose of this study is to accumulate preclinical rationales to establish appropriate treatment sequences by clarifying the change of tumor immune microenvironment (TIME) and molecular patterns in approved molecular targeted agents (MTA) and locoregional treatment, hepatic arterial infusion chemotherapy (HAIC) using cisplatin and 5-fluorouracil.
Methods
We established immune syngeneic orthotopic HCC mouse models and treated them with each approved MTA (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) to evaluate the change of TIME in each drug. We also compared the therapeutic effects of atezolizumab plus bevacizumab (AB) with and without the pretreatment of HAIC. Moreover, we evaluated the influence of HAIC on HCC using the resected specimens in clinical samples.
Results
All MTAs commonly reduced infiltration of regulatory T cells and macrophages, which suggested that these changes were induced by the inhibition of VEGF signaling. Cabozantinib particularly induced the infiltration of dendritic cells, and lenvatinib significantly increased the infiltration of cytotoxic T cells and granzyme B-positive cells, which suggested that TIME has altered to a "hot" environment. To clarify why lenvatinib altered the TIME to "hot", experiments using a pan-FGF receptor inhibitor were conducted. The FGF receptor inhibitor also increased the infiltration of cytotoxic T cells and granzyme B-positive cells. Taken together, these results suggest that inhibition of the FGF signal is important to the alteration of TIME to "hot".
The therapeutic response (objective response rate: with or w/o pretreatment HAIC; 60.8% v.s. 29.7%, p<0.001), progression-free survival (median; 5.5 months v.s., 5.2 months, p<0.05), and overall survival (median; 12.7 months v.s. 9.9 months, p<0.05) of patients treated with AB were superior in the pretreatment HAIC group. The expression of PD-L1 was significantly increased in HCC specimens treated with HAIC before hepatic resection. Cisplatin and 5-fluorouracil directly induced the expression of PD-L1 in human hepatoma cell lines.
Conclusions
Lenvatinib had promising effects to alter TIME to an immune "hot" environment and HAIC might have another role as a neo-adjuvant treatment to enhance the therapeutic effects of treatments using immune checkpoint inhibitors.
Accumulation of preclinical rationales leads to establishing appropriate sequential treatments in the era of chemo-diversity for HCC.
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