Brief intro:
- Author: Taral R. Lunavat, Sanne M. van de Looij, Charles P. Couturier, Tyler E. Miller, Maryam Schübel, Emilio Di Ianni, Yi Sun, Thomas S. van Solinge, Emily Grandell, Vamsi Mangena, Russell W. Jenkins, Xandra O. Breakefield, Koen Breyne
- Journal: bioRxiv
- Publication Date: 2025 Feb 5
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 CD8POS 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 CD8POS 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.
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