2018
DOI: 10.1055/s-0038-1673621
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Immunomodulatory Effects of Current Targeted Therapies on Hepatocellular Carcinoma: Implication for the Future of Immunotherapy

Abstract: Multikinase inhibitors with antiangiogenic properties used to be standard therapy for patients with advanced hepatocellular carcinoma (HCC). Recently, several antiangiogenic agents (lenvatinib, cabozantinib, and ramucirumab) have demonstrated antitumor activity for advanced HCC in randomized controlled trials. However, the landscape of drug development for HCC may change dramatically with the advent of immune checkpoint inhibitor therapy, particularly the anti–programmed cell death-1 (anti-PD1) agents. In addi… Show more

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Cited by 66 publications
(52 citation statements)
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“…In vitro and in vivo preclinical studies have provoked the thoughts that there may be different immunomodulatory effects among similar tyrosine kinase inhibitors [34]. Lenvatinib may decrease tumor-associated macrophages, facilitate polarization from an M2-like phenotype toward an M1-like phenotype, and enhance CD4 + and CD8 + T-cell tumor infiltration, while sorafenib may have the opposite effects [35]. In our previous study of sorafenib [21], 11 of 16 soluble immune checkpoint proteins-most of which were inhibitory factors-experienced significant increases in plasma at two weeks of treatment.…”
Section: Discussionmentioning
confidence: 99%
“…In vitro and in vivo preclinical studies have provoked the thoughts that there may be different immunomodulatory effects among similar tyrosine kinase inhibitors [34]. Lenvatinib may decrease tumor-associated macrophages, facilitate polarization from an M2-like phenotype toward an M1-like phenotype, and enhance CD4 + and CD8 + T-cell tumor infiltration, while sorafenib may have the opposite effects [35]. In our previous study of sorafenib [21], 11 of 16 soluble immune checkpoint proteins-most of which were inhibitory factors-experienced significant increases in plasma at two weeks of treatment.…”
Section: Discussionmentioning
confidence: 99%
“…98 Lower dosages (<30 mg/kg in vivo or <3 lM in vitro) appeared to be associated with a higher likelihood of inducing beneficial immunomodulatory effects, while higher dosages were immunosuppressive through induction of hypoxia and recruitment of MDSCs, TAMs, or other suppressive cells. [99][100][101] (Fig. 1).…”
Section: The Importance Of Predictive Biomarkersmentioning
confidence: 96%
“…Previous studies in melanoma and nonsmall cell lung cancer patients have demonstrated that treatment efficacy varies according to the location of the organs involved and the occurrence of immune cells in the metastatic tumors [5]. Response patterns to immunotherapies are clinically important because they can provide further information regarding clinical treatment practices and may help differentiate individuals with oligoprogressive disease who may require additional locoregional or combination therapies [6]. Thus, considering the increasing ICI literature related to HCC treatment, concrete data on tumor response to immunotherapies for different organ sites in HCC patients in clinical settings are unavailable.…”
Section: Introductionmentioning
confidence: 99%