Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma
Osteosarcoma is the most frequent and aggressive bone tumor in children and adolescents, with a long-term survival rate of 30%. Interleukin-12 (IL-12) is a potent cytokine that bridges innate and adaptive immunity, triggers antiangiogenic responses, and achieves potent antitumor effects. In this wor...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770520301686 |
| _version_ | 1818734290258624512 |
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| author | Marta Zalacain María Bunuales Lucía Marrodan Sara Labiano Marisol Gonzalez-Huarriz Naiara Martinez-Vélez Virginia Laspidea Montse Puigdelloses Marc García-Moure Manuela Gonzalez-Aparicio Rubén Hernandez-Alcoceba Marta M. Alonso Ana Patiño-García |
| author_facet | Marta Zalacain María Bunuales Lucía Marrodan Sara Labiano Marisol Gonzalez-Huarriz Naiara Martinez-Vélez Virginia Laspidea Montse Puigdelloses Marc García-Moure Manuela Gonzalez-Aparicio Rubén Hernandez-Alcoceba Marta M. Alonso Ana Patiño-García |
| author_sort | Marta Zalacain |
| collection | DOAJ |
| description | Osteosarcoma is the most frequent and aggressive bone tumor in children and adolescents, with a long-term survival rate of 30%. Interleukin-12 (IL-12) is a potent cytokine that bridges innate and adaptive immunity, triggers antiangiogenic responses, and achieves potent antitumor effects. In this work, we evaluated the antisarcoma effect of a high-capacity adenoviral vector encoding mouse IL-12. This vector harbored a mifepristone-inducible system for controlled expression of IL-12 (High-Capacity adenoviral vector enconding the EF1α promoter [HCA-EFZP]-IL-12). We found that local administration of the vector resulted in a reduction in the tumor burden, extended overall survival, and tumor eradication. Moreover, long-term survivors exhibited immunological memory when rechallenged with the same tumor cells. Treatment with HCA-EFZP-IL-12 also resulted in a significant decrease in lung metastasis. Immunohistochemical analyses showed profound remodeling of the osteosarcoma microenvironment with decreases in angiogenesis and macrophage and myeloid cell numbers. In summary, our data underscore the potential therapeutic value of IL-12 in the context of a drug-inducible system that allows controlled expression of this cytokine, which can trigger a potent antitumor immune response in primary and metastatic pediatric osteosarcoma. |
| first_indexed | 2024-12-18T00:03:00Z |
| format | Article |
| id | doaj.art-31c2c8191c8240cdb76ac36ee4d1b26d |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-18T00:03:00Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-31c2c8191c8240cdb76ac36ee4d1b26d2022-12-21T21:27:54ZengElsevierMolecular Therapy: Oncolytics2372-77052021-03-01202333Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcomaMarta Zalacain0María Bunuales1Lucía Marrodan2Sara Labiano3Marisol Gonzalez-Huarriz4Naiara Martinez-Vélez5Virginia Laspidea6Montse Puigdelloses7Marc García-Moure8Manuela Gonzalez-Aparicio9Rubén Hernandez-Alcoceba10Marta M. Alonso11Ana Patiño-García12Health Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, SpainHealth Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, Spain; Corresponding author: Marta M. Alonso, PhD, Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, Spain.Health Research Institute of Navarra (IDISNA), 31008 Pamplona, Navarra, Spain; Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Navarra, Spain; Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, Spain; Corresponding author: Ana Patiño-García, Department of Pediatrics, Clínica Universidad de Navarra, 31008 Pamplona, Spain.Osteosarcoma is the most frequent and aggressive bone tumor in children and adolescents, with a long-term survival rate of 30%. Interleukin-12 (IL-12) is a potent cytokine that bridges innate and adaptive immunity, triggers antiangiogenic responses, and achieves potent antitumor effects. In this work, we evaluated the antisarcoma effect of a high-capacity adenoviral vector encoding mouse IL-12. This vector harbored a mifepristone-inducible system for controlled expression of IL-12 (High-Capacity adenoviral vector enconding the EF1α promoter [HCA-EFZP]-IL-12). We found that local administration of the vector resulted in a reduction in the tumor burden, extended overall survival, and tumor eradication. Moreover, long-term survivors exhibited immunological memory when rechallenged with the same tumor cells. Treatment with HCA-EFZP-IL-12 also resulted in a significant decrease in lung metastasis. Immunohistochemical analyses showed profound remodeling of the osteosarcoma microenvironment with decreases in angiogenesis and macrophage and myeloid cell numbers. In summary, our data underscore the potential therapeutic value of IL-12 in the context of a drug-inducible system that allows controlled expression of this cytokine, which can trigger a potent antitumor immune response in primary and metastatic pediatric osteosarcoma.http://www.sciencedirect.com/science/article/pii/S2372770520301686Pediatric solid tumorstherapyosteosarcomahigh capacity adenoviral vectorsimmunotherapyIL-12 |
| spellingShingle | Marta Zalacain María Bunuales Lucía Marrodan Sara Labiano Marisol Gonzalez-Huarriz Naiara Martinez-Vélez Virginia Laspidea Montse Puigdelloses Marc García-Moure Manuela Gonzalez-Aparicio Rubén Hernandez-Alcoceba Marta M. Alonso Ana Patiño-García Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma Molecular Therapy: Oncolytics Pediatric solid tumors therapy osteosarcoma high capacity adenoviral vectors immunotherapy IL-12 |
| title | Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma |
| title_full | Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma |
| title_fullStr | Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma |
| title_full_unstemmed | Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma |
| title_short | Local administration of IL-12 with an HC vector results in local and metastatic tumor control in pediatric osteosarcoma |
| title_sort | local administration of il 12 with an hc vector results in local and metastatic tumor control in pediatric osteosarcoma |
| topic | Pediatric solid tumors therapy osteosarcoma high capacity adenoviral vectors immunotherapy IL-12 |
| url | http://www.sciencedirect.com/science/article/pii/S2372770520301686 |
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