Combination Cancer Immunotherapy in Hepatocellular Carcinoma

Kudo, Masatoshi

doi:10.1159/000486487

Cited by 65 publications

(55 citation statements)

References 24 publications

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“…However, the clinical benefit over placebo was observed similar to that observed in KEYNOTE-224. The effect of pembrolizumab in combination with lenvatinib is currently being assessed in a phase III study [30] (LEAP-002; NCT: 03713593). Therefore, the results of the LEAP-002 trial are eagerly awaited.…”

Section: Resultsmentioning

confidence: 99%

“…The synergistic effects and mode of action of combining lenvatinib with pembrolizumab were demonstrated in animal studies [29, 30], and the rationale is as follows. Voron et al [31] reported that VEGF-A released by tumors and the vascular endothelium at the tumor site promotes the formation of various immune suppressive cells such as tumor-associated macrophages (TAMs), Tregs, or myeloid-derived suppressor cells, which creates an immunosuppressive microenvironment that induces tumor immune escape.…”

Section: Combination Immunotherapy With Pembrolizumab and Lenvatinibmentioning

confidence: 99%

“…A trial assessing pembrolizumab in combination with lenvatinib (LEAP-002) is currently ongoing as a phase III study [30] (NCT: 03713593). This combination is the most promising treatment approach among combination therapies using various immune checkpoint inhibitors and antiangiogenic agents [30] (Table 5; Fig.…”

Section: Combination Immunotherapy With Pembrolizumab and Lenvatinibmentioning

confidence: 99%

“…This combination is the most promising treatment approach among combination therapies using various immune checkpoint inhibitors and antiangiogenic agents [30] (Table 5; Fig. 3).…”

Section: Combination Immunotherapy With Pembrolizumab and Lenvatinibmentioning

confidence: 99%

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Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Kudo

2019

Liver Cancer

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Section: Resultsmentioning

confidence: 99%

Section: Combination Immunotherapy With Pembrolizumab and Lenvatinibmentioning

confidence: 99%

Section: Combination Immunotherapy With Pembrolizumab and Lenvatinibmentioning

confidence: 99%

“…This combination is the most promising treatment approach among combination therapies using various immune checkpoint inhibitors and antiangiogenic agents [30] (Table 5; Fig. 3).…”

Section: Combination Immunotherapy With Pembrolizumab and Lenvatinibmentioning

confidence: 99%

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Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Kudo

2019

Liver Cancer

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“…Combination therapies of anti-PD-1/anti-PD-L1 antibodies with other MTAs or with other immune checkpoint inhibitors such as anti-CTLA-4 agents may bring a much better survival in HCC patients and lead to a paradigm shift in the treatment strategy for this disease. The recent development of immune checkpoint inhibitors [19], multiple MTAs [20], and combination therapies as described above [21] may lead to major innovations in the treatment of HCC in the very near future. Further drug development based on an improved understanding of the mechanisms of action of combination therapy should substantially improve the prognosis of patients with unresectable HCC.…”

Section: Resultsmentioning

confidence: 99%

Combination Cancer Immunotherapy with Molecular Targeted Agents/Anti-CTLA-4 Antibody for Hepatocellular Carcinoma

Kudo¹

2019

Liver Cancer

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Cancer‐associated fibroblasts nurture LGR5 marked liver tumor‐initiating cells and promote their tumor formation, growth, and metastasis

Zhang

Fang

et al. 2023

Cancer Medicine

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Background & AimsIn liver cancer, leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) compartment represents an important tumor‐initiating cell (TIC) population and served as a potential therapeutic target. Cancer‐associated fibroblasts (CAFs) is a critical part of the tumor microenvironment, heavily influenced TIC function and fate. However, deeply investigations have been hindered by the lack of accurate preclinical models to investigate the interaction between CAFs and TIC. Organoids model have achieved major advancements as a precious research model for recapitulating the morphological aspects of organs, and thus also serving as a candidate model to investigate the mutual interaction between different cell types. Consequently, this study aimed to construct a three‐dimensional (3D) co‐culture organoid model of primary LGR5‐expressing tumor stem cells from primary murine liver tumors with CAFs to investigate the impact of CAFs on LGR5 marked TICs in liver cancer.Materials and MethodsFirst, both of the transgenic LGR5‐diphtheria toxin receptor (DTR)‐GFP knock‐in mice and transgenic Rosa26‐mT mice developed primary liver tumors by diethylnitrosamine (DEN) administration. Tumor organoids and CAFs were generated from those primary liver cancer separately. Second, LGR5‐expressing TICs organoid with CAFs were established ex vivo based on cell–cell contact or trans‐well co‐culture system, and the mutual influence between those two types of cells was further investigated. Subsequently, immunodeficient mouse‐based xenograft model was further adopted to evaluate the influence of CAFs to LGR5 tumor stem cell, tumor formation, and metastasis.ResultsThe co‐culture organoid model composed of murine liver tumor LGR5+ tumor‐initiating cells and CAFs in 3D co‐culture was successfully established, with the intention to investigate their mutual interaction. The existence of CAFs upon engrafting tumor organoids resulted in dramatic higher number of LGR5+ cells in the neoplasia when compared with engrafting tumor organoids alone. Furthermore, ex vivo culture of isolated LGR5+ cells from tumors of co‐engrafted mice formed significantly larger size of organoids than mono‐engrafted. Our results also indicated significantly larger size and number of formed organoids, when LGR5+ cells co‐cultured with CAF in both cell–cell contact and paracrine signaling in vitro, comparing to LGR5+ cells alone. Furthermore, we found that specific knockout of LGR5 expressing cells suppressed CAF‐mediated promotion of tumor formation, growth, and metastasis in the experimental mice model.ConclusionsAltogether, in a 3D co‐culture type of murine liver LGR5+ cells and cancer‐associated fibroblasts, we have demonstrated robust effects of CAFs in the promotion of LGR5 marked liver TICs. We also further revealed the influence of tumor microenvironment on stem cell‐related therapy, suggesting the possibility of combing CAF‐targeted and tumor stem cell targeted therapy in treating liver cancer.

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Combination Cancer Immunotherapy in Hepatocellular Carcinoma

Cited by 65 publications

References 24 publications

Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Pembrolizumab for the Treatment of Hepatocellular Carcinoma

Combination Cancer Immunotherapy with Molecular Targeted Agents/Anti-CTLA-4 Antibody for Hepatocellular Carcinoma

Cancer‐associated fibroblasts nurture LGR5 marked liver tumor‐initiating cells and promote their tumor formation, growth, and metastasis

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