Efficacy of an Oncolytic Adenovirus Driven by a Chimeric Promoter and Armed with Decorin Against Renal Cell Carcinoma

Tian

et al. 2020

Cell Biosci

Background Glioblastoma (GBM) is an immunosuppressive, highly vascular and devastating malignant brain tumor. Even with progressive combination treatment that includes surgery, radiotherapy, and chemotherapy, the prognosis for GBM patients is still extremely poor. Oncolytic adenovirus (OAd) can specifically replicate in GBM cells, permitting the rapid copy of the therapeutic genes it carries. Moreover, E1A is an essential gene in adenoviral replication and is the first gene expressed upon viral infection. E1A expression can be regulated by the Ki67 promoter, while the CMV promoter drives therapeutic gene expression. However, the efficacy of a double-controlled OAd driven by the Ki67 core promoter and armed with IL-15 against GBM cells has not been investigated. Methods Fluorescence microscopy was performed to evaluate infection ability in the viruses. Cell viability was detected by CCK-8 assay. Levels of cytokines in different supernatants were determined by ELISA, and IL-15 gene expression was measured by RT-PCR. Angiogenic capacity was analyzed by tube formation assay. Results We successfully constructed a double-controlled oncolytic adenovirus driven by the Ki67 core promoter and armed with IL-15 that selectively infected and killed GBM cells while sparing normal cells. The adenoviruses prime IL-15 gene expression to significantly enhance anti-GBM efficacy through effective activation of microglial cells. Moreover, OAd not only directly inhibits angiogenesis but exhibits potent antiangiogenic capacity mediated by the reduction of VEGF secretion. Conclusions These results provide new insight into the effects of a novel double-controlled OAd driven by the Ki67 core promoter and armed with IL-15 in glioblastoma treatment, which may help in the development of novel therapies in solid tumors.

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of a novel double-controlled oncolytic adenovirus driven by the Ki67 core promoter and armed with IL-15 against glioblastoma cells

Tian

et al. 2020

Cell Biosci

“…An engineered oncolytic adenovirus expressing decorin named OAV-Decorin (OAV-DEC) was constructed previously, 33 in the backbone of a tumor-selective oncolytic adenovirus ZD55 vector, in which E1B-55KD had been deleted. HEK293 cells were used to amplify virus OAV-DEC or control vector virus OAV with a density of about 80%, when half of the cells were floated, the viruses were collected and the titers were measured by tissue culture infection dose 50 (TCID50) methods.…”

Section: Methodsmentioning

confidence: 99%

Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma

Molecular Therapy - Oncolytics

Lin

Wang

et al. 2022

Self Cite

Although chimeric antigen receptor T cell (CAR-T) therapy has been successful for hematological malignancies, it is less effective for solid tumors. The primary reason is that the immune microenvironment restricts CAR-T cells from infiltrating and proliferating in tumors. Oncolytic virotherapy has emerged as a novel immunogenic therapy to augment antitumor immune response. Here we combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) to perform the antitumor activity for renal cancer cells. We found that OAV-Decorin combined with CAIX-CAR-T exhibited significantly reduced tumor burden, altered the composition of extracellular matrix (ECM) by inhibiting the distribution of collagen fibers, decreased the expression of TGF-β in tumor cells, enhanced IFN-γ secretion, and obtained higher numbers of CAR-T cells. The combination treatment modality showed prolonged mice survival. The intratumoral injection of OAV-Decorin into tumor-bearing immunocompetent mice activated the inflammatory immune status and resulted in tumor regression. These data supported further investigation of the combination of OAV-Decorin and CAIX-CAR-T cells in solid tumors.

“…During infections, viruses hijack host cells replication mechanisms, promote their own genetic expression, and unavoidably cause the death of host cells, allowing viral offspring to reach and infect neighboring host cells ( Martinez-Velez et al, 2019 ). OVs can specifically infect and kill tumor cells and have become an attractive treatment choice ( Fang et al, 2014 ; Martikainen and Essand, 2019 ; Zhang W. et al, 2020 ). Our research team has showed that OVs have potent therapeutic efficacy and safety to treat malignant brain glioma and uveal melanoma ( Zhang J. et al, 2020 ; Liu et al, 2020a ; Zhang Q. et al, 2020 ; Liu et al, 2020b ; Liu et al, 2021 ).…”

Section: Potential Clinical Applicationsmentioning

confidence: 99%

Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

Zhu

et al. 2021

Front. Pharmacol.

Chimeric antigen receptor T cells (CAR-T) therapy is a prospective therapeutic strategy for blood cancers tumor, especially leukemia, but it is not effective for solid tumors. Glioblastoma (GBM) is a highly immunosuppressive and deadly malignant tumor with poor responses to immunotherapies. Although CAR-T therapeutic strategies were used for glioma in preclinical trials, the current proliferation activity of CAR-T is not sufficient, and malignant glioma usually recruit immunosuppressive cells to form a tumor microenvironment that hinders CAR-T infiltration, depletes CAR-T, and impairs their efficacy. Moreover, specific environments such as hypoxia and nutritional deficiency can hinder the killing effect of CAR-T, limiting their therapeutic effect. The normal brain lack lymphocytes, but CAR-T usually can recognize specific antigens and regulate the tumor immune microenvironment to increase and decrease pro- and anti-inflammatory factors, respectively. This increases the number of T cells and ultimately enhances anti-tumor effects. CAR-T therapy has become an indispensable modality for glioma due to the specific tumor-associated antigens (TAAs). This review describes the characteristics of CAR-T specific antigen recognition and changing tumor immune microenvironment, as well as ongoing research into CAR-T therapy targeting TAAs in GBM and their potential clinical application.