Virus, Vessel, Victory: A Novel Approach to Tumor Killing

Bykov, Yonina; Zamarin, Dmitriy

doi:10.1158/1078-0432.ccr-18-3441

Cited by 3 publications

(2 citation statements)

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“…14 In addition to improving the immunosuppressive TME, targeting VEGF can also enhance blood flow in the main vessels and reduce hypoxia within the tumor mass, leading to significant improvements in drug delivery. 15 In this study, we constructed a double-gene recombinant oncolytic adenovirus, RCAd-LTH-shPD-L1, with a DNA fragment encoding an anti-VEGF antibody and shRNA to inhibit PD-L1 expression. After assessing the biological activity of RCAd-LTH-shPD-L1 in vitro, we examined its antitumor effect in vivo, not only in nude mice, but also in human peripheral blood mononuclear cells (PBMCs) engrafted in severely immunodeficient M-NSG mice (humanized immune system mouse model) to more closely mimic human antitumor immune responses.…”

Section: What This Study Addsmentioning

confidence: 99%

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RCAd-LTH-shPD-L1, a double-gene recombinant oncolytic adenovirus with enhanced antitumor immunity, increases lymphocyte infiltration and reshapes the tumor microenvironment

Meng,

Liu,

Zhu

et al. 2024

J Immunother Cancer

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BackgroundWith the successful development of modern immunotherapy, immune checkpoint inhibitors (ICIs) are currently considered potential therapeutic options for patients with cancer. However, the therapeutic potential of ICIs in human cancer is mainly limited by their systemic toxicity and low response rate, which suggests the necessity of local drug delivery with an effective vector and reshaping the immunosuppressive tumor microenvironment (TME) to enhance ICI therapy. Here, we constructed a novel double-gene recombinant oncolytic adenovirus named RCAd-LTH-shPD-L1 based on the RCAd virus platform armed with a DNA fragment encoding an anti-VEGF antibody and shRNA to inhibit PD-L1 expression.MethodsThe correct assembly of RCAd-LTH-shPD-L1 was characterized by analyzing its secretion, antigen specificity, and replication using western blotting, ELISA and quantitative PCR, respectively. The in vitro effects of RCAd-LTH-shPD-L1 on cell proliferation, vasculogenic, and cell migration were assessed. Antitumor effects and therapeutic mechanisms were evaluated in vivo using immunodeficient and humanized immune system mouse models. The TME was studied by ELISA, immunohistochemistry and flow cytometry.ResultsRCAd-LTH-shPD-L1 cells secreted anti-VEGF antibodies and inhibited the expression of PD-L1 in cancer cells. Moreover, RCAd-LTH-shPD-L1 exerted a specific cytotoxic effect on human cancer cells, but not on murine cancer cells or normal human cells. RCAd-LTH-shPD-L1 elicited a more potent antitumor effect in an immunodeficient mouse model and a humanized immune system mouse model than RCAd-shPD-L1, as demonstrated by the significant decrease in tumor growth. Furthermore, RCAd-LTH-shPD-L1 modulated the TME, which led to lymphocyte infiltration and alteration of their immune phenotype, as characterized by downregulation of anoxic factor HIF-1α and angiogenesis marker CD31, upregulation of cytokine such as IFN-γ, IL-6 and IL-12.ConclusionsIn summary, our data demonstrated that the localized delivery of anti-VEGF antibodies and shPD-L1 by engineered RCAd-LTH-shPD-L1 is a highly effective and safe strategy for cancer immunotherapy. Moreover, the data underscore the potential of combining local virotherapy and anti-angiogenic therapy with ICIs as an effective TME therapy for poorly infiltrating tumors.

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Section: What This Study Addsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%