Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer

Wang, Fei; Sun, Haoran; Huang, Yakai; Gao, Jianpeng; Huang, Hua

doi:10.1007/s00432-021-03633-3

Cited by 15 publications

(9 citation statements)

References 42 publications

(53 reference statements)

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“…Combination therapy induced HEVs formation by activating LTβR signaling, thus promoting the infiltration of CD8 + cytotoxic T cells and CD20 + B cells in the tumor. The results synergistically delayed the tumor growth and improved survival in gastric cancer mice ( 97 ). Anti-angiogenesis can prevent metastasis, improve immunotherapy, enhance drug penetration, and reshape the TME ( 23 , 98 , 99 ).…”

Section: Molecular Mechanismsmentioning

confidence: 99%

“…In another immunocompetent mice model of subcutaneous MFC tumors study, combined treatment with apatinib and PD-L1 blockade synergistically delayed tumor growth and improved survival rates in MFC tumor-bearing immunocompetent mice. It is explained that combined apatinib and PD-L1 blockage treatment synergistically promotes HEV formation and enhances antitumor immune responses in gastric cancer ( 97 ). Further, in the co-culture system, apatinib-treated cancer cells upregulated PD-L1 expression and angiogenesis inhibition, and hindered T cell activation and IFN-γ secretion, which was reversed by an anti-PD-1 antibody.…”

Section: Molecular Mechanismsmentioning

confidence: 99%

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Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies

Huang

Zhang

et al. 2022

Front. Immunol.

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Digestive system malignancies are one of the primary causes of cancer-related death. Meanwhile, angiogenesis has been proved to play an important role in the process of cancer neovascularization. Apatinib, a novel targeted antiangiogenic molecule, could generate highly selective competition in the vascular endothelial growth factor receptor-2, involved in tumor progression and metastasis. It has been implied as a promising cancer treatment agent that can prevent tumor cell proliferation meanwhile inhibit tumor angiogenesis. Furthermore, completed clinical trials demonstrated that apatinib could prolong the progression-free survival and overall survival in advanced gastric cancer and primary liver cancer. Recent studies revealed that apatinib had a synergistic effect with immunotherapy as a second-line and third-line treatment regimen for some other cancers. In this review, we summarize the pharmacological properties of apatinib and the latest clinical application in chemotherapy-refractory patients with advanced digestive system cancer. Based on the comparable survival results, the molecular mechanisms of apatinib are prospective to include the antiangiogenic, apoptosis-inducing, and autophagy-inducing properties in the corresponding signaling pathway. Treatment of apatinib monotherapy or combination immunotherapy remains the optimal option for patients with digestive system malignancies in the future.

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Section: Molecular Mechanismsmentioning

confidence: 99%

Section: Molecular Mechanismsmentioning

confidence: 99%

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies

Huang

Zhang

et al. 2022

Front. Immunol.

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“…Helper T (Th) cells, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells that have been activated can all generate interferon (IFN), which can then activate the JAK/STAT pathway and lead to PD-L1 expression. In the meantime, IL-10 can boost PD-L1 expression ( 12 , 18 ). Moreover, the C > G variant of the rs4143815 SNP in the 3’-UTR of the PD-L1 gene increases PD-L1 expression and may increase cancer risk ( 19 ).…”

Section: The Mechanism Of Immune Evasionmentioning

confidence: 99%

The mechanisms on evasion of anti-tumor immune responses in gastric cancer

et al. 2022

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The immune system and the tumor have been at each other’s throats for so long that the neoplasm has learned to avoid detection and avoid being attacked, which is called immune evasion. Malignant tumors, such as gastric cancer (GC), share the ability to evade the body’s immune system as a defining feature. Immune evasion includes alterations to tumor-associated antigens (TAAs), antigen presentation mechanisms (APMs), and the tumor microenvironment (TME). While TAA and APM are simpler in nature, they both involve mutations or epigenetic regulation of genes. The TME is comprised of numerous cell types, cytokines, chemokines and extracellular matrix, any one of which might be altered to have an effect on the surrounding ecosystem. The NF-kB, MAPK, PI3K/AKT, JAK/STAT, Wnt/β-catenin, Notch, Hippo and TGF-β/Smad signaling pathways are all associated with gastric cancer tumor immune evasion. In this review, we will delineate the functions of these pathways in immune evasion.

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“…Apatinib is an oral multi-target drug which could block VEGFR-2 and inhibit tumor growth and metastasis ( 10 , 13 ). Interestingly, one study has shown combined apatinib and PD-L1 blockade therapy synergistically enhances antitumor immune responses and promotes high endothelial venules formation in GC ( 14 ). Another study has shown PD-1 inhibitor combined with apatinib could modulate the tumor microenvironment and potentiate anti-tumor effect in mice bearing GC ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Apatinib combined with PD-1 antibody for third-line or later treatment of advanced gastric cancer

Cui

Mao²,

Wu³

et al. 2022

Front. Oncol.

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BackgroundBoth apatinib and programmed death 1 (PD-1) monoclonal antibody (mAb) monotherapy have been licensed in China for the third-line treatment of advanced gastric cancer (AGC). However, whether the combination could improve the prognosis of patients with AGC after second-line treatment has not been evaluated.MethodsWe retrospectively screened 892 patients with AGC who received third-line or later treatment from June 2016 to July 2021 at the Affiliated Cancer Hospital of Zhengzhou University and second People’s Hospital of Pingdingshan. 166 patients who received apatinib plus PD-1 mAb, apatinib, or PD-1 mAb were included. Based on medical records and follow-up data, we analyzed the efficacy and safety of these three treatment options.ResultsPatients received apatinib plus PD-1 mAb (n=49), apatinib monotherapy (n=63), or PD-1 mAb monotherapy (n=54). Apatinib plus PD-1 mAb showed significantly longer progression-free survival (PFS) and overall surivival (OS) compared with the apatinib monotherapy (PFS: 5.5 months versus 3.0 months; p=0.002; OS: 10 months versus 7.6 months; p=0.011) or PD-1 mAb monotherapy (PFS: 5.5 months versus 2.3 months; p=0.017; OS: 10 months versus 6.5 months; p=0.004). Apatinib plus PD-1 mAb showed higher ORR and DCR than the apatinib and PD-1 mAb monotherapy (ORR: 34.7% versus 6.3% versus 9.3%; p=0.001; DCR: 75.5% versus 44.4% versus 40.7%; p=0.001). Further subgroup analysis for PFS and OS shown consistent efficacy in most subgroups with apatinib plus PD-1 mAb versus apatinib monotherapy or PD-1 mAb monotherapy. Multivariate analyses suggested that apatinib plus PD-1 mAb was significantly associated with better PFS and OS. Most of the treatment-related toxicities were mild and tolerable.ConclusionCompared with the monotherapy of either apatinib or PD-1 mAb, apatinib plus PD-1 mAb treatment yielded longer PFS and OS, and achieved significant higher ORR and DCR.

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Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer

Cited by 15 publications

References 42 publications

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies

Apatinib: A Novel Antiangiogenic Drug in Monotherapy or Combination Immunotherapy for Digestive System Malignancies

The mechanisms on evasion of anti-tumor immune responses in gastric cancer

Apatinib combined with PD-1 antibody for third-line or later treatment of advanced gastric cancer

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