Oncolytic adenovirus co-expressing IL-12 and shVEGF potentiates immune checkpoint blockade for treatment of renal cell carcinoma: in vitro, organ-on-a-chip, and in vivo evaluation
Abstract
Renal cell carcinoma (RCC) has been known as highly malignant and resistant to standard therapy due to its immunosuppressive tumor microenvironment and aberrant VEGF-mediated angiogenesis. To overcome these therapeutic limitations, here we assessed the therapeutic efficacy of an oncolytic adenovirus (oAd) co-expressing Interleukin-12 (IL-12) and a short hairpin RNA against VEGF (shVEGF) in combination with immune checkpoint inhibitors (ICIs). The oAd/IL12/shVEGF induced RCC-specific cancer cell death in vitro and 3D bioprinted model, leading to greater anti-tumor effect compared with oAd-GMCSF. Furthermore, it potentiates anti-tumor efficacy in RCC orthotopic tumor model. The potent antitumor effect induced by combination of oAd/IL12/shVEGF with anti-PD1 was due to CD4 + or CD8 + T cell- or NK cell-mediated antitumor immune response and effective inhibition of tumor-associated neovascularization. Collectively, oAd/IL12/shVEGF can be a potent strategy to overcome current limitations in conventional RCC therapy by converting the cold tumor microenvironment to an inflamed state to sensitize refractory tumors to ICIs. Multifaceted antitumor effects of oAd/IL12/shVEGF combined with anti-PD1 therapy in renal cell carcinoma. The therapeutic efficacy of this combination strategy was evaluated using in vitro, 3D bioprinted, and in vivo RCC models. oAd/IL12/shVEGF induces virus-mediated oncolysis and the release of tumor antigens, while IL-12 promotes antitumor immune activation and…
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