Intratumoral delivery of 4-1BBL boosts IL-12-triggered anti-glioma immunity.

Molecular therapy : the journal of the American Society of Gene Therapy
Authors
Keywords
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 for patients with glioma. Here, we demonstrate that intratumoral (i.t.) administration of recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8 T cell accumulation and conversion into an effector-like state, resulting in a dose-dependent survival benefit in preclinical glioblastoma (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 in both cell types. Given that DCs and CD8 T cells are functionally suppressed in the tumor microenvironments (TME) 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-1 2-treated GB-bearing mice. This study establishes that tumor antigen (Ag)-specific CD8 T cell activity can be augmented by incorporating an AAV-vector-mediated gene therapy approach, effectively enhancing anti-GB immunity in the TME.

Year of Publication
2025
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Date Published
08/2025
ISSN
1525-0024
DOI
10.1016/j.ymthe.2025.08.028
PubMed ID
40842154
Links