Targeting the CD40 Costimulatory Receptor To Improve Virotherapy Efficacy in Diffuse Midline Gliomas

Authors

Sara Labiano
Javier Marco-Sanz
Iker Ausejo-Mauleon
Virginia Laspidea
Reyes Hernández-Osuna
Marc Garcia-Moure
Daniel de la Nava
Sara Nuin
Marisol Gonzalez-Huarriz
Timothy N Phoenix
Ibon Tamayo
Marta Zalacain
Andrea Lacalle
Lucía Marrodan
Montserrat Puigdelloses
Irati Hervás-Corpión
Maria C Ochoa
Noelia Casares
Oren J Becher
Candelaria Gomez-Manzano
Juan Fueyo
Jaime Gallego Perez-Larraya
Ana Patiño-Garcia
Marta M Alonso

Publication Date

7-15-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2025.102204

PMID

40578365

PMCID

PMC12281365

PubMedCentral® Posted Date

6-26-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and proinflammatory myeloid cells, including mature DCs with superior tumor antigen uptake capacity. Moreover, the lack of cross-presenting DCs and the prevention of DC recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-DMG effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.

Keywords

CD40 Antigens, Glioma, Animals, Humans, Dendritic Cells, Oncolytic Virotherapy, Mice, Brain Neoplasms, Cell Line, Tumor, Female, Adenoviridae, Mice, Inbred C57BL, diffuse midline glioma, DMG, diffuse intrinsic pontine glioma, DIPG, oncolytic adenovirus, Delta-24-RGD, CD40, dendritic cells

Published Open-Access

yes

Recommended Citation

Labiano, Sara; Marco-Sanz, Javier; Ausejo-Mauleon, Iker; et al., "Targeting the CD40 Costimulatory Receptor To Improve Virotherapy Efficacy in Diffuse Midline Gliomas" (2025). Faculty, Staff and Student Publications. 4388.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4388