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.

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.