Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy
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 adenovir...
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Elsevier
2024-09-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S295032992400105X |
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| author | Alvaro Morales-Molina Miguel Angel Rodriguez-Milla Patricia Garcia-Rodriguez Laura Hidalgo Ramon Alemany Javier Garcia-Castro |
| author_facet | Alvaro Morales-Molina Miguel Angel Rodriguez-Milla Patricia Garcia-Rodriguez Laura Hidalgo Ramon Alemany Javier Garcia-Castro |
| author_sort | Alvaro Morales-Molina |
| collection | DOAJ |
| description | 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 in vitro 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 in vivo 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. |
| format | Article |
| id | doaj-art-f889f634fb8d45d19137a418f077a9bb |
| institution | Kabale University |
| issn | 2950-3299 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-f889f634fb8d45d19137a418f077a9bb2024-11-24T04:15:47ZengElsevierMolecular Therapy: Oncology2950-32992024-09-01323200863Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapyAlvaro Morales-Molina0Miguel Angel Rodriguez-Milla1Patricia Garcia-Rodriguez2Laura Hidalgo3Ramon Alemany4Javier Garcia-Castro5Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, SpainCellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, SpainCellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain; Universidad Nacional de Educación a Distancia, UNED, 28015 Madrid, SpainCellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, SpainOncobell and ProCure Programs, IDIBELL-Institut Català d’Oncologia, L’Hospitalet de Llobregat, 08908 Barcelona, SpainCellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain; Instituto de Investigación de Enfermedades Raras (IIER) & Departamento de Desarrollo de Medicamentos de Terapias Avanzadas (DDMTA), Instituto de Salud Carlos III, 28220 Madrid, Spain; Corresponding author: Javier Garcia-Castro, Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain.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 in vitro 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 in vivo 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.http://www.sciencedirect.com/science/article/pii/S295032992400105Xoncolytic virusRGDpenton baseadenovirusNKG2DT cell |
| spellingShingle | Alvaro Morales-Molina Miguel Angel Rodriguez-Milla Patricia Garcia-Rodriguez Laura Hidalgo Ramon Alemany Javier Garcia-Castro Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy Molecular Therapy: Oncology oncolytic virus RGD penton base adenovirus NKG2D T cell |
| title | Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy |
| title_full | Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy |
| title_fullStr | Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy |
| title_full_unstemmed | Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy |
| title_short | Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy |
| title_sort | deletion of the rgd motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined car t cell therapy |
| topic | oncolytic virus RGD penton base adenovirus NKG2D T cell |
| url | http://www.sciencedirect.com/science/article/pii/S295032992400105X |
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