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

Kudo, Masatoshi

doi:10.1159/000496277

Cited by 55 publications

(44 citation statements)

References 21 publications

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“…TAM targeting, in turn, can be achieved by barricading the colony stimulating factor 1 receptor (CSF1R), which is essential for the recruitment, differentiation and survival of TAM [103] (Fig. 2c) [104]. Inhibitors of CSF1R can reduce TAM or cause phenotypic alterations that might hinder the growth and progression of cancer cells [92,[105][106][107].…”

Section: Cancer-associated Fibroblast (Cafs)mentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices.

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Section: Cancer-associated Fibroblast (Cafs)mentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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“…The most extensively tested combination regimen for advanced HCC comprises anti-PD1/anti-PDL1 plus antiangiogenic agents. 16 All of the approved targeted therapies for the treatment of advanced HCC (sorafenib and lenvatinib in the first line; regorafenib, cabozantinib, and ramucirumab in the second line) have antiangiogenic effects that are considered critical for antitumor efficacy in HCC. 17 In recent years, both pre-clinical models and clinical trials demonstrated the immunomodulatory effects of antiangiogenic agents in the tumour microenvironment, including enhancement of dendritic cell maturation, T cell trafficking and function, and reversal of immunosuppression caused by tissue hypoxia and immunosuppressive cells, such as tumour-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloidderived suppressor cells (MDSCs).…”

Section: Promising Data On Immuno-oncology Combinations For Advanced Hccmentioning

confidence: 99%

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

Cheng

Hsu

Chan

et al. 2020

Journal of Hepatology

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378

339

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Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immunooncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.

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“…Currently, the tyrosine kinase inhibitors (TKI) sorafenib and lenvatinib are the first-line treatments in advanced HCC [5][6][7][8]. Regorafenib, nivolumab, cabozantinib, and ramucirumab were approved as second line therapies following their recent successes in several clinical trials [9][10][11][12][13][14][15]. Despite these breakthroughs, many patients still do not survive advanced HCC.…”

Section: Introductionmentioning

confidence: 99%

“…These immunological features enable HCC to benefit from immunotherapy. Thus, harnessing these immune characters through combination immunotherapy is proposed as the next important step in treatment of advanced HCC [4,[13][14][15]21,22].…”

Section: Introductionmentioning

confidence: 99%

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

Park

Lee³

et al. 2020

Cancers

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The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.

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

Cited by 55 publications

References 21 publications

Tumor microenvironment complexity and therapeutic implications at a glance

Tumor microenvironment complexity and therapeutic implications at a glance

Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

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