Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

Leong, Leonard W.; Tan, Heng Liang; Cua, Simeon; Yong, Kylie Su Mei; Chen, Yi‐Ping Phoebe; Choo, Andre

doi:10.3390/ijms21020381

Cited by 18 publications

(19 citation statements)

References 40 publications

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“…AnxA2 antibody-conjugated and curcumin-loaded nanoparticles effectively accumulated in tumours, providing sustained release of curcumin with potential to reduce metastatic breast cancer progression [ 163 ]. A monoclonal AnxA2 antibody not only allowed monitoring EMT in breast and ovarian cancers, but also provided antibody-dependent cell toxicity and efficient killing when conjugated to cytotoxic drugs and expressed as a chimeric immunoglobulin G1 [ 164 , 165 , 166 ]. Other beneficial effects of AnxA2 antibodies include the inhibition of neoangiogenesis in TNBC xenograft models, which involves reduced plasmin generation as well as loss of AnxA2 tyrosine 23 phosphorylation [ 167 , 168 ].…”

Section: Anxa2mentioning

confidence: 99%

Annexin Animal Models—From Fundamental Principles to Translational Research

Grewal

Rentero

Enrich

et al. 2021

IJMS

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Routine manipulation of the mouse genome has become a landmark in biomedical research. Traits that are only associated with advanced developmental stages can now be investigated within a living organism, and the in vivo analysis of corresponding phenotypes and functions advances the translation into the clinical setting. The annexins, a family of closely related calcium (Ca2+)- and lipid-binding proteins, are found at various intra- and extracellular locations, and interact with a broad range of membrane lipids and proteins. Their impacts on cellular functions has been extensively assessed in vitro, yet annexin-deficient mouse models generally develop normally and do not display obvious phenotypes. Only in recent years, studies examining genetically modified annexin mouse models which were exposed to stress conditions mimicking human disease often revealed striking phenotypes. This review is the first comprehensive overview of annexin-related research using animal models and their exciting future use for relevant issues in biology and experimental medicine.

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Section: Anxa2mentioning

confidence: 99%

Annexin Animal Models—From Fundamental Principles to Translational Research

Grewal

Rentero

Enrich

et al. 2021

IJMS

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“…Another factor that may impact the activity of CAR-T cells is the spatial conformation of extracellular domains. Leonard Leong et al verified that the structure of the part behind the antigen-recognize region and its length could affect the activity of CAR-T cells [32]. Based on this finding, the cytotoxicity of CAR-T cells may be related to the composition and spatial conformation of extracellular domains.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of dual CAR-T targeting PDL1 and MUC16 antigens on ovarian cancer cells in mice

Wang

2020

BMC Cancer

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Background: More favorable treatment against epithelial ovarian cancer (EOC) is urgently needed because of its insidious nature at an early stage and a low rate of five-year survival. The current primary treatment, extensive surgery combined with chemotherapy, exhibits limited benefits for improving prognosis. Chimeric antigen receptor T (CAR-T) cell technology as novel immunotherapy has made breakthrough progress in the treatment of hematologic malignancies, and there were also benefits shown in a partial solid tumor in previous research. Therefore, CART cell technology may be a promising candidate as an immunotherapeutic tool against EOC. However, there are some weaknesses in targeting one antigen from the previous preclinical assay, such as ontarget off-tumor cytotoxicity. The dual-target CART cell may be a better choice. Methods: We constructed tandem PD1-antiMUC16 dual-CAR, PD1 single-CAR, and anti-MUC16 single-CAR fragments by PCR and genetic engineering, followed by preparing CART cells via lentiviral infection. The expression of CAR molecules on single and dual CART cells was detected by flow cytometry. The killing capacity and activation of CART cells were measured by cytotoxic assays and cytokines release assays in vitro. The therapeutic capacity of CART cells was assessed by tumor-bearing mice model assay in vivo. Results: We successfully constructed CARs lentiviral expression vectors and obtained single and dual CART cells. CART cells demonstrated robust killing capacity against OVCAR-3 cells in vitro. Meanwhile, CART cells released plenty of cytokines such as interleukin-2(IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α(TNF-α). CART cells showed a therapeutic benefit against OVCAR-3 tumor-bearing mice and significantly prolonged the survival time. Dual CART cells were shown to be two to four times more efficacious than single CART cells in terms of survival time. Conclusion: Although exhibiting a similar ability as single CART cells against OVCAR-3 cells in vitro, dual CART cells demonstrated enhanced killing capacity against OVCAR-3 cells as compared to single CART cells in vivo and significantly prolonged the survival time of tumor-bearing mice. PD1-antiMUC16 CART cells showed more potent antitumor activity than single CART cells in vivo. The present experimental data may support further research work that will have the potential to lead to clinical studies.

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“…Another factor that may impact the activity of CAR-T cells is the spatial conformation of extracellular domains. Leonard Leong et al veri ed that the structure of the part behind the antigen-recognize region and its length could affect the activity of CAR-T cells [32]. Based on this nding, the cytotoxicity of CAR-T cells may be related to the composition and spatial conformation of extracellular domains.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effect of Dual CAR-T Targeting PDL1 and MUC16 Antigens on Ovarian Cancer Cells in Mice

Wang²

2020

Preprint

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Background: More favorable treatment against epithelial ovarian cancer (EOC) is urgently needed because of its insidious nature at an early stage and a low rate of five-year survival. The current primary treatment, extensive surgery combined with chemotherapy, exhibits limited benefits for improving prognosis. Chimeric antigen receptor T (CAR-T) cell technology as novel immunotherapy has made breakthrough progress in the treatment of hematologic malignancies, and there were also benefits shown in a partial solid tumor in previous research. Therefore, CAR-T cell technology may be a promising candidate as an immunotherapeutic tool against EOC. However, there are some weaknesses in targeting one antigen from the previous preclinical assay, such as on-target off-tumor cytotoxicity. The dual-target CAR-T cell may be a better choice.Methods: We constructed tandem PD1-antiMUC16 dual-CAR, PD1 single-CAR, and anti-MUC16 single-CAR fragments by PCR and genetic engineering, followed by preparing CAR-T cells via lentiviral infection. The expression of CAR molecules on single and dual CAR-T cells was detected by flow cytometry. The killing capacity and activation of CAR-T cells were measured by cytotoxic assays and cytokines release assays in vitro. The therapeutic capacity of CAR-T cells was assessed by tumor-bearing mice model assay in vivo.Results: We successfully constructed CARs lentiviral expression vectors and obtained single and dual CAR-T cells. CAR-T cells demonstrated robust killing capacity against OVCAR-3 cells in vitro. Meanwhile, CAR-T cells released plenty of cytokines such as interleukin-2(IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α(TNF-α). CAR-T cells showed a therapeutic benefit against OVCAR-3 tumor-bearing mice and significantly prolonged the survival time. Dual CAR-T cells were shown to be two to four times more efficacious than single CAR-T cells in terms of survival time. Conclusion: Although exhibiting a similar ability as single CAR-T cells against OVCAR-3 cells in vitro, dual CAR-T cells demonstrated enhanced killing capacity against OVCAR-3 cells as compared to single CAR-T cells in vivo and significantly prolonged the survival time of tumor-bearing mice. PD1-antiMUC16 CAR-T cells showed more potent antitumor activity than single CAR-T cells in vivo. The present experimental data may support further research work that will have the potential to lead to clinical studies.

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Preclinical Activity of Embryonic Annexin A2-Specific Chimeric Antigen Receptor T Cells Against Ovarian Cancer

Cited by 18 publications

References 40 publications

Annexin Animal Models—From Fundamental Principles to Translational Research

Annexin Animal Models—From Fundamental Principles to Translational Research

Therapeutic effect of dual CAR-T targeting PDL1 and MUC16 antigens on ovarian cancer cells in mice

Therapeutic Effect of Dual CAR-T Targeting PDL1 and MUC16 Antigens on Ovarian Cancer Cells in Mice

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