A VEGFR2–MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice

Xu, Yao; Zhang, Juan; Wang, Yong; Pan, Mingzhu; Wang, Min

doi:10.1007/s00262-019-02379-9

Cited by 11 publications

(8 citation statements)

References 39 publications

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“…The anti-tumor roles of high PD-L1 on TICs for ovarian patients was also illustrated in other cancers, including colorectal ( 77 ), breast ( 78 ) and high-grade neuroendocrine carcinoma of lung ( 79 ). Its anti-cancer effects may be related with an adaptive mechanism to further activate and increase levels of cytotoxic CD8+ T cells as well as tumor-infiltrating lymphocytes ( 78 , 80 – 82 ). Also, there was a study of non-small cell lung cancer to report that PD-L1 expression on tumor cells and TICs was associated with high levels of M2 tumor-associated macrophages and then led to a poor prognosis and an aggressive malignant phenotype, which may be one potential reason to cause the tumor-promoting effects of PD-L1 on tumor cells and TICs for gynecological cancers ( 83 , 84 ).…”

Section: Discussionmentioning

confidence: 99%

Predictive Values of Programmed Cell Death-Ligand 1 Expression for Prognosis, Clinicopathological Factors, and Response to Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors in Patients With Gynecological Cancers: A Meta-Analysis

Zhang

Yang

2021

Front. Oncol.

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BackgroundThe prognostic value of programmed cell death-ligand 1 (PD-L1) in gynecological cancers has been explored previously, but the conclusion remains controversial due to limited evidence. This study aimed to conduct an updated meta-analysis to re-investigate the predictive significance of PD-L1 expression.MethodsPubMed, EMBASE and Cochrane Library databases were searched. The associations between PD-L1 expression status and prognosis [overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), cancer-specific survival (CSS) or disease-free survival (DFS)], clinical parameters [FIGO stage, lymph node metastasis (LNM), tumor size, infiltration depth, lymphovascular space invasion (LVSI) or grade] and response to anti-PD-1/PD-L1 treatment [objective response rate (ORR)] were analyzed by hazard ratios (HR) or relative risks (RR).ResultsFifty-five studies were enrolled. Overall, high PD-L1 expression was not significantly associated with OS, PFS, RFS, CSS and DFS of gynecological cancers. However, subgroup analysis of studies with reported HR (HR = 1.27) and a cut-off value of 5% (HR = 2.10) suggested that high PD-L1 expression was correlated with a shorter OS of gynecological cancer patients. Further sub-subgroup analysis revealed that high PD-L1 expressed on tumor-infiltrating immune cells (TICs) predicted a favorable OS for ovarian (HR = 0.72), but a poor OS for cervical cancer (HR = 3.44). PD-L1 overexpression was also correlated with a lower OS rate in non-Asian endometrial cancer (HR = 1.60). High level of PD-L1 was only clinically correlated with a shorter PFS in Asian endometrial cancer (HR = 1.59). Furthermore, PD-L1-positivity was correlated with LNM (for overall, ovarian and endometrial cancer expressed on tumor cells), advanced FIGO stage (for overall, ovarian cancer expressed on tumor cells, endometrial cancer expressed on tumor cells and TICs), LVSI (for overall and endometrial cancer expressed on tumor cells and TICs), and increasing infiltration depth/high grade (only for endometrial cancer expressed on TICs). Patients with PD-L1-positivity may obtain more benefit from anti-PD-1/PD-L1 treatment than the negative group, showing a higher ORR (RR = 1.98), longer OS (HR = 0.34) and PFS (HR = 0.61).ConclusionOur findings suggest high PD-L1 expression may be a suitable biomarker for predicting the clinical outcomes in patients with gynecological cancers.

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Section: Discussionmentioning

confidence: 99%

Predictive Values of Programmed Cell Death-Ligand 1 Expression for Prognosis, Clinicopathological Factors, and Response to Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors in Patients With Gynecological Cancers: A Meta-Analysis

Zhang

Yang

2021

Front. Oncol.

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“…53 Xu et al also designed a designed an antivascular endothelial growth factor receptor 2 (VEGFR2)-MICA bispecific antibody. 54 It effectively reduced the tumor vascular density, and increased the infiltration and activation of NK and CD8 þ T cells within the tumor microenvironment. The VEGFR2-MICA bispecific antibody showed enhanced antitumor efficacy against mouse non-small cell lung cancer when combined with docetaxel or liposomal doxorubicin 54,55 .…”

Section: Future Directions Of Mica-targeted Therapy For Hccmentioning

confidence: 99%

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

Arai,

Okumura,

Kato

et al. 2024

Hepatology Research

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The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%–50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta‐analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome‐wide association study on chronic viral hepatitis showed that a single‐nucleotide polymorphism of major histocompatibility complex class I polypeptide‐related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single‐nucleotide polymorphism‐driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane‐bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell‐mediated cytotoxicity.

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“…In the mouse lung cancer model, the use of low-dose Apatinib increased the infiltration of CD8 + T cells in tumors [22] . Comprehensive studies have shown that blocking VEGFR-2 could increase the proportion and activity of CD8 + T cells [23,24] . Moreover, low-dose VEGFR-2 target drug (DC101) is more conducive to promoting the tumor infiltration of CD4 + and CD8 + T cells [25] .…”

Section: Effect Of Apatinib On the Immune Microenvironment 31 Effect Of Apatinib On Effector T Cellsmentioning

confidence: 99%

Combination of anti-angiogenic therapy Apatinib and immune therapy potentiate tumor microenvironment

Gao

2021

Trends Immunother

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Tumor immune therapy, especially anti-programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1) treatment, is currently the focus of substantial attention. However, despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal. There is an increased interest in combining PD-L1/PD-1 treatment with anti-angiogenic drug Apatinib to enhance antitumor effect. Presently available data seem to suggest that Apatinib may exert immune suppressive effects to make the PD-L1/PD-1 treatment works. Here, we review the extensive tumor microenvironment immune modulatory effects from antiangiogenic agents Apatinib in order to supporting VEGFR2 targettherapies in clinical trials are existing.

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A VEGFR2–MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice

Cited by 11 publications

References 39 publications

Predictive Values of Programmed Cell Death-Ligand 1 Expression for Prognosis, Clinicopathological Factors, and Response to Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors in Patients With Gynecological Cancers: A Meta-Analysis

Predictive Values of Programmed Cell Death-Ligand 1 Expression for Prognosis, Clinicopathological Factors, and Response to Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors in Patients With Gynecological Cancers: A Meta-Analysis

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

Combination of anti-angiogenic therapy Apatinib and immune therapy potentiate tumor microenvironment

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