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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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | Molecular Therapy: Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329925000712 |
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| Summary: | 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. |
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| ISSN: | 2950-3299 |