Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model
Interleukin-12 (IL-12) is a promising pro-inflammatory cytokine for cancer immunotherapy, but its toxicity and short half-life in serum limit its clinical application. Tumor-targeted delivery of IL-12 by fusion with either antibody or secretion by chimeric antigen receptor T (CAR-T) cells showed red...
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| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329925000712 |
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| author | Chuyuan Chen Yongji Jiang Chuan Feng Qingyun Zhou Xingrong Luo Lili Cai Lei Zhao |
| author_facet | Chuyuan Chen Yongji Jiang Chuan Feng Qingyun Zhou Xingrong Luo Lili Cai Lei Zhao |
| author_sort | Chuyuan Chen |
| collection | DOAJ |
| description | Interleukin-12 (IL-12) is a promising pro-inflammatory cytokine for cancer immunotherapy, but its toxicity and short half-life in serum limit its clinical application. Tumor-targeted delivery of IL-12 by fusion with either antibody or secretion by chimeric antigen receptor T (CAR-T) cells showed reduced systematic toxicity; however, the poor tumor microenvironment (TME) response or the lack of systematic IL-12 regulation still remains risk of low efficacy or high toxicity. Here, we developed TME-specific delivery of IL-12 by a tumor-targeted adeno-associated virus 9 (tAAV9). The tAAV9 was formed by an anti-folate receptor 1 (anti-FOLR1) antibody fragment conjugated with AAV9 via highly efficient Spy-ligation. With targeted infection of FOLR1+ cells in vivo, intravenous (i.v.) administration of tAAV9 specifically delivered IL-12 (tAAV9-IL-12) to TME and significantly suppressed tumor progression with favorable safety profile compared with rAAV9 (recombinant wild-type AAV9) delivery. Moreover, the IL-12 level in the serum was decreased significantly with the suppression of tAAV9-IL-12-infected tumor cell, so that generates promising negative feedback to ensure the safety profile. |
| format | Article |
| id | doaj-art-258969ffc4b9428caa20782a52e3554c |
| institution | OA Journals |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-258969ffc4b9428caa20782a52e3554c2025-08-20T02:03:25ZengElsevierMolecular Therapy: Oncology2950-32992025-06-0133220100210.1016/j.omton.2025.201002Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse modelChuyuan Chen0Yongji Jiang1Chuan Feng2Qingyun Zhou3Xingrong Luo4Lili Cai5Lei Zhao6Department of Gene Therapy, Cure Genetics Co., LTD, Suzhou, ChinaDepartment of Gene Therapy, Cure Genetics Co., LTD, Suzhou, ChinaDivision of Research & Development, Department of Cell Therapy, Cure Genetics Co., LTD, Suzhou, ChinaDepartment of Gene Therapy, Cure Genetics Co., LTD, Suzhou, ChinaDepartment of Gene Therapy, Cure Genetics Co., LTD, Suzhou, ChinaDepartment of Gene Therapy, Cure Genetics Co., LTD, Suzhou, ChinaDepartment of Gene Therapy, Cure Genetics Co., LTD, Suzhou, China; Corresponding author: Lei Zhao, Department of Gene Therapy, Cure Genetics Co., LTD, Suzhou, China.Interleukin-12 (IL-12) is a promising pro-inflammatory cytokine for cancer immunotherapy, but its toxicity and short half-life in serum limit its clinical application. Tumor-targeted delivery of IL-12 by fusion with either antibody or secretion by chimeric antigen receptor T (CAR-T) cells showed reduced systematic toxicity; however, the poor tumor microenvironment (TME) response or the lack of systematic IL-12 regulation still remains risk of low efficacy or high toxicity. Here, we developed TME-specific delivery of IL-12 by a tumor-targeted adeno-associated virus 9 (tAAV9). The tAAV9 was formed by an anti-folate receptor 1 (anti-FOLR1) antibody fragment conjugated with AAV9 via highly efficient Spy-ligation. With targeted infection of FOLR1+ cells in vivo, intravenous (i.v.) administration of tAAV9 specifically delivered IL-12 (tAAV9-IL-12) to TME and significantly suppressed tumor progression with favorable safety profile compared with rAAV9 (recombinant wild-type AAV9) delivery. Moreover, the IL-12 level in the serum was decreased significantly with the suppression of tAAV9-IL-12-infected tumor cell, so that generates promising negative feedback to ensure the safety profile.http://www.sciencedirect.com/science/article/pii/S2950329925000712MT: Regular Issuecell specific AAVinterleukin-12tumor microenvironmentsolid tumorgene therapy |
| spellingShingle | Chuyuan Chen Yongji Jiang Chuan Feng Qingyun Zhou Xingrong Luo Lili Cai Lei Zhao Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model Molecular Therapy: Oncology MT: Regular Issue cell specific AAV interleukin-12 tumor microenvironment solid tumor gene therapy |
| title | Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model |
| title_full | Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model |
| title_fullStr | Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model |
| title_full_unstemmed | Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model |
| title_short | Tumor-specific AAV delivery of interleukin-12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model |
| title_sort | tumor specific aav delivery of interleukin 12 enhances antitumor immunity and safety in ovarian cancer xenograft mouse model |
| topic | MT: Regular Issue cell specific AAV interleukin-12 tumor microenvironment solid tumor gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2950329925000712 |
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