Oncolytic cytomegaloviruses expressing EGFR-retargeted fusogenic glycoprotein complex and drug-controllable interleukin 12.

Abstract

Cytomegalovirus (CMV) infects a wide range of cell types, including tumor-associated myeloid cells and glioma cells. Clinical observations suggest a potential link between long-term glioblastoma survival and CMV reactivation. We herein present an oncolytic CMV vector, AD169r, which includes a restored pentamer complex gH/gL/pUL128-131 and the removal of UL1-UL20 and UL/b' sequences. The epidermal growth factor receptor (EGFR)-retargeted paramyxoviral glycoprotein H/F complexes are incorporated into AD169r backbone to enhance viral oncolysis. Additionally, a tet-off-controlled single-chain interleukin (IL)-12 is added to boost antitumor immune responses. The engineered oncolytic CMVs expressing EGFR-retargeted H/F complex demonstrate enhanced antitumor efficacy in human glioblastoma xenograft models. In the immunocompetent mouse CT-2A glioblastoma model, an oncolytic murine CMV (mCMV) expressing IL-12 significantly increases the abundance and cytotoxicity of CD4⁺ T cells, CD8⁺ T cells, and CD4^-CD8^- T cells in both treated and untreated tumors. Our findings highlight the potential of the AD169r-derived oncolytic viruses as CMV-based cancer viroimmunotherapy.