Deletion of RGD-motif from penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy

Abstract

Oncolytic viruses often face challenges in achieving optimal antitumor immunity as standalone therapies. The penton base RGD-integrin interactions play a significant fi cant 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 fi cial RGD motifs in the fi ber knobs. ISC301 demonstrated comparable in vitro infectivity, cytotoxic effects, and signaling profiles fi les across various cell types to its parental ICOVIR-5, which retains the penton base RGD motif. In immunodeficient fi cient and immunocompetent mouse models, ISC301 exhibited similar in vivo antitumor efficacy fi cacy to ICOVIR-5. However, ISC301 induced higher intratumoral inflammation fl ammation through NF-KB K B activation, leading to increased levels of tumor-infiltrating fi ltrating leukocytes and higher proportion of cytotoxic CD8+ + T cells. In addition, ISC301 elicits a heightened pro-inflammatory fl ammatory response in peripheral blood. Importantly, when combined with CAR T cell therapy, ISC301 exhibited superior antitumor efficacy, fi cacy, surpassing monotherapy outcomes. These fi ndings emphasize the impact of adenoviral modifications fi cations on antitumor immune responses. The deletion of penton base RGD motifs enhances ISC301's ' s pro-inflammatory fl ammatory profile fi le and boosts CART cell therapy efficacy. fi cacy. This study enhances understanding of oncolytic virus engineering strategies, positioning ISC301 as a promising candidate for combined immunotherapeutic approaches in cancer treatment.