Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors
Abstract Background A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and...
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2024-11-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03219-0 |
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| author | Elise Jirovec Dafne C. A. Quixabeira James H. A. Clubb Santeri A. Pakola Tatiana Kudling Victor Arias Lyna Haybout Katriina Jalkanen Tuomo Alanko Tine Monberg Amir Khammari Brigitte Dreno Inge Marie Svane Matthew S. Block Daniel A. Adamo Johanna Mäenpää Claudia Kistler Suvi Sorsa Otto Hemminki Anna Kanerva João M. Santos Victor Cervera-Carrascon Akseli Hemminki |
| author_facet | Elise Jirovec Dafne C. A. Quixabeira James H. A. Clubb Santeri A. Pakola Tatiana Kudling Victor Arias Lyna Haybout Katriina Jalkanen Tuomo Alanko Tine Monberg Amir Khammari Brigitte Dreno Inge Marie Svane Matthew S. Block Daniel A. Adamo Johanna Mäenpää Claudia Kistler Suvi Sorsa Otto Hemminki Anna Kanerva João M. Santos Victor Cervera-Carrascon Akseli Hemminki |
| author_sort | Elise Jirovec |
| collection | DOAJ |
| description | Abstract Background A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials. Methods Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period. Results Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405). Conclusion TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation. Trial registrations TUNIMO—NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL—NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA—NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 . |
| format | Article |
| id | doaj-art-45e8bf709efc4b58a91d86132c2c2011 |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-45e8bf709efc4b58a91d86132c2c20112025-08-20T02:13:32ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-11-0143111510.1186/s13046-024-03219-0Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumorsElise Jirovec0Dafne C. A. Quixabeira1James H. A. Clubb2Santeri A. Pakola3Tatiana Kudling4Victor Arias5Lyna Haybout6Katriina Jalkanen7Tuomo Alanko8Tine Monberg9Amir Khammari10Brigitte Dreno11Inge Marie Svane12Matthew S. Block13Daniel A. Adamo14Johanna Mäenpää15Claudia Kistler16Suvi Sorsa17Otto Hemminki18Anna Kanerva19João M. Santos20Victor Cervera-Carrascon21Akseli Hemminki22Cancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiComprehensive Cancer Center, Helsinki University HospitalDocrates Cancer CenterNational Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University HospitalDepartment of Dermatology, Nantes University, CHU Nantes, CIC1413, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302Nantes University, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University HospitalMayo Clinic Cancer CenterMayo Clinic Cancer CenterDocrates Cancer CenterTILT Biotherapeutics LtdTILT Biotherapeutics LtdCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiCancer Gene Therapy Group, Translational Immunology Research Program, University of HelsinkiAbstract Background A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials. Methods Patients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period. Results Across all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405). Conclusion TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation. Trial registrations TUNIMO—NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327 . TUNINTIL—NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473 . PROTA—NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318 .https://doi.org/10.1186/s13046-024-03219-0Oncolytic VirusTILT-123Intravenous DeliveryAdenovirusSolid TumorsImmunotherapy |
| spellingShingle | Elise Jirovec Dafne C. A. Quixabeira James H. A. Clubb Santeri A. Pakola Tatiana Kudling Victor Arias Lyna Haybout Katriina Jalkanen Tuomo Alanko Tine Monberg Amir Khammari Brigitte Dreno Inge Marie Svane Matthew S. Block Daniel A. Adamo Johanna Mäenpää Claudia Kistler Suvi Sorsa Otto Hemminki Anna Kanerva João M. Santos Victor Cervera-Carrascon Akseli Hemminki Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors Journal of Experimental & Clinical Cancer Research Oncolytic Virus TILT-123 Intravenous Delivery Adenovirus Solid Tumors Immunotherapy |
| title | Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors |
| title_full | Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors |
| title_fullStr | Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors |
| title_full_unstemmed | Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors |
| title_short | Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors |
| title_sort | single intravenous administration of oncolytic adenovirus tilt 123 results in systemic tumor transduction and immune response in patients with advanced solid tumors |
| topic | Oncolytic Virus TILT-123 Intravenous Delivery Adenovirus Solid Tumors Immunotherapy |
| url | https://doi.org/10.1186/s13046-024-03219-0 |
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