Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation

Intratumoral gene delivery of 4-1BBL boosts IL-12-triggered anti-glioblastoma immunity

Taral R Lunavat et al. bioRxiv. .

Update in

  • Intratumoral delivery of 4-1BBL boosts IL-12-triggered anti-glioma immunity.
    Lunavat TR, Nieland L, van de Looij SM, de Reus AJEM, Couturier CP, El Farran CA, Miller TE, Lill JK, Schübel M, Xiao T, Di Ianni E, Woods EC, Sun Y, Rufino-Ramos D, van Solinge TS, Mahjoum S, Grandell E, Li M, Mangena V, Dunn GP, Jenkins RW, Mempel TR, Breakefield XO, Breyne K. Lunavat TR, et al. Mol Ther. 2025 Aug 20:S1525-0016(25)00658-6. doi: 10.1016/j.ymthe.2025.08.028. Online ahead of print. Mol Ther. 2025. PMID: 40842154 Free PMC article.

Abstract

The standard of care in high-grade gliomas has remained unchanged in the past 20 years. Efforts to replicate effective immunotherapies in non-cranial tumors have led to only modest therapeutical improvements in glioblastoma (GB). Here, we demonstrate that intratumoral administration of recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8 POS T cell accumulation and conversion into an effector-like state, resulting in a dose-dependent survival benefit in preclinical GB mouse models. This tumor-reactive CD8 T cell response is further supported by intratumoral rIL-12-sensing dendritic cells (DCs) and is accompanied by the co-stimulatory receptor 4-1BB expression on both cell types. Given that DCs and CD8 POS T cells are functionally suppressed in the tumor microenvironments of de novo and recurrent glioma patients, we tested whether anti-tumor response at the rIL-12-inflamed tumor site could be enhanced with 4-1BBL, the ligand of 4-1BB. 4-1BBL was delivered using an adeno-associated virus (AAV) vector targeting GFAP-expressing cells and resulted in prolonged survival of rIL-12 treated GB-bearing mice. This study establishes that tumor antigen-specific CD8 T cell activity can be directed using an AAV-vector-mediated gene therapy approach, effectively enhancing anti-GB immunity.

PubMed Disclaimer

Publication types