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00925njm 22002777a 4500 dc Morales-Molina, Alvaro author Rodriguez-Milla, Miguel A author García-Rodriguez, Patricia author Hidalgo, Laura author Alemany, Ramon author Garcia-Castro, Javier author 2024-09-19 Oncolytic viruses often face challenges in achieving optimal antitumor immunity as standalone therapies. The penton base RGD-integrin interactions play a significant role in wild-type adenovirus-induced innate immune responses. To modify these responses, we present ISC301, a novel oncolytic adenovirus engineered by deleting the natural RGD motifs in the penton base while incorporating artificial RGD motifs in the fiber knobs. ISC301 demonstrated comparable infectivity, cytotoxic effects, and signaling profiles across various cell types to its parental ICOVIR-5, which retains the penton base RGD motif. In immunodeficient and immunocompetent mouse models, ISC301 exhibited similar antitumor efficacy to ICOVIR-5. However, ISC301 induced higher intratumoral inflammation through NF-κB activation, leading to increased levels of tumor-infiltrating leukocytes and higher proportion of cytotoxic CD8 T cells. In addition, ISC301 elicits a heightened pro-inflammatory response in peripheral blood. Importantly, when combined with CAR T cell therapy, ISC301 exhibited superior antitumor efficacy, surpassing monotherapy outcomes. These findings emphasize the impact of adenoviral modifications on antitumor immune responses. The deletion of penton base RGD motifs enhances ISC301's pro-inflammatory profile and boosts CAR T cell therapy efficacy. This study enhances understanding of oncolytic virus engineering strategies, positioning ISC301 as a promising candidate for combined immunotherapeutic approaches in cancer treatment. Mol Ther Oncol . 2024 Aug 23;32(3):200863 10.1016/j.omton.2024.200863 2950-3299 Molecular Therapy Oncology 39290319 https://hdl.handle.net/20.500.12105/25077 CAR T NKG2D RGD T cell Adenovirus Immunotherapy Oncolytic virus Penton base Virotherapy Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy