Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Hato, Tai; Zhu, Andrew X.; Duda, Dan G.

doi:10.2217/imt.15.126

Cited by 128 publications

(106 citation statements)

References 95 publications

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“…These effects may involve transient normalization of the vascular structure and function as well as pronounced vascular rarefaction, which have been proven critical for the metastatic progression of tumors as well as for AA interactions with cytotoxic drugs . These effects remain unclear in HCC, a disease where several AAs are standard . The potential of AAs to enhance antitumor immunity when combined with immunotherapy in patients has been postulated by others and us by diverse mechanisms based on data from preclinical models, which all converged to normalization of tumor vessels and microenvironment as a principle .…”

Section: Discussionmentioning

confidence: 99%

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2019

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Background and Aims Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD‐1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and Results We recapitulated these clinical outcomes using orthotopic—grafted or induced—murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR‐2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti‐PD‐1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti‐PD‐1/VEGFR‐2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8–positive (CD8+) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor‐associated macrophages and reducing T regulatory cell (Treg) and chemokine (C‐C motif) receptor 2–positive monocyte infiltration in HCC tissue. In these models, VEGFR‐2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD‐ligand 1 expression in HCC cells was induced in a paracrine manner upon anti‐VEGFR‐2 blockade in endothelial cells in part through interferon‐gamma expression. Moreover, we found that VEGFR‐2 blockade increased PD‐1 expression in tumor‐infiltrating CD4+ cells. We also found that under anti‐PD‐1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti‐VEGFR‐2 antibody. Conclusions We show that dual anti‐PD‐1/VEGFR‐2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti‐PD‐1 therapy–resistant and anti‐PD‐1 therapy–responsive HCC models.

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Section: Discussionmentioning

confidence: 99%

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

et al. 2019

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“…By its regulation to angiogenesis gene, endostatin can inhibit proliferation, migration or invasion and apoptosis of endothelial cells, to play antineoplastic activity (27). It has been approved to cure or retreatment Ⅲ/Ⅳ stage non-small cell lung cancer combined with NP chemotherapy (NP regimen includes Navelbine (25 (28,29). mDCs from peripheral blood of cancer patients are associated with increased serum levels of VEGF.…”

Section: Discussionmentioning

confidence: 99%

Endostatin reverses immunosuppression of the tumor microenvironment in lung carcinoma

et al. 2017

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Abstract.Endostatin has previously been demonstrated to efficiently inhibit the angiogenesis and growth of endothelial cells. However, the role of endostatin in the tumor microenvironment remains to be elucidated. To investigate the antitumor effect of endostatin in lung cancer, the present study was designed to explore the alterations of microvessel density in Lewis lung cancer models and the expression of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-17, interferon (IFN)-γ and hypoxia inducible factor (HIF)-1α, following endostatin therapy. It was demonstrated that the growth and angiogenesis of tumors were markedly suppressed by treatment with endostatin, compared with control group. The microvessel density in mice treated with endostatin was significantly inhibited in a dose-dependent manner. The expression levels of VEGF, IL-6 and IL-17 in tumors were decreased, however IFN-γ and HIF-1α expression levels were increased, following treatment with endostatin. In addition, the proportion of myeloid derived suppressor cells and tumor associated macrophages (TAMs; M2 type) were significantly decreased, whereas those of mature dendritic cells and TAMs (M1 type) were increased, and cluster of differentiation (CD)8 + T cells were recruited to infiltrate the tumors following treatment with endostatin. In addition, the expression levels of IL-6, IL-10, tumor growth factor-β and IL-17 in tumor tissue were potently decreased with endostatin therapy. These results indicated that endostatin efficiently inhibited tumor angiogenesis and reversed the immunosuppressive microenvironment associated with the presence of tumors.

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“…Elevated levels are found in a vast variety of tissues when put at risk of tissue-threatening ischemia, e.g. in heart (myocardial infarction),24 brain (stroke),25 muscle (peripheral arterial occlusive disease),26 liver (tumor, infarction)27 and kidney (infarction) 28. While VEGF causes both long- and short-term tissue protective effects in healthy tissue, its effects in tumorous tissues include, but are not limited to, faster and more profound metastatic seeding, as well as regeneration and growth of malignant tissues 16–18…”

Section: Discussionmentioning

confidence: 99%

Impact of Different Embolic Agents for Transarterial Chemoembolization (TACE) Procedures on Systemic Vascular Endothelial Growth Factor (VEGF) Levels

Schicho

Hellerbrand

Krüger

et al. 2016

JCTH

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Background and Aims: Intermediate stage hepatocellular carcinoma (HCC) can be treated by transarterial chemoembolization (TACE). However, there appear to be side effects, such as induction of proangiogenic factors, e.g. vascular endothelial growth factor (VEGF), which have been shown to be associated with a poor prognosis. This prospective study was designed to compare serum VEGF level response after TACE with different embolic agents in patients with HCC.Methods: Patients were assigned to one of three different TACE regimens: degradable starch microspheres (DSM) TACE, drug-eluting bead (DEBDOX) TACE or Lipiodol TACE (cTACE). All patients received 50 mg doxorubicin/m2 body surface area (BSA) during TACE. Serum VEGF levels were assessed before TACE treatment, 24 h post-treatment and 4 weeks later.Results: Twenty-two patients with 30 TACE treatments were enrolled. Compared to baseline VEGF levels, a marked increase was observed for 24 h post-TACE (164% of baseline level) and during the 4-week follow-up (170% of baseline level) only for the cTACE arm (p < 0.05). In contrast, the increase of serum VEGF levels were only 114% and 123% for DEBDOX and 121% and 124% for DSM, respectively.Conclusions: Conventional TACE using Lipiodol shows marked increase in blood levels of the proangiogenic factor VEGF, while DEBDOX and DSM TACE induce only a moderate VEGF response.

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Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Cited by 128 publications

References 95 publications

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

Endostatin reverses immunosuppression of the tumor microenvironment in lung carcinoma

Impact of Different Embolic Agents for Transarterial Chemoembolization (TACE) Procedures on Systemic Vascular Endothelial Growth Factor (VEGF) Levels

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