Targeting the CD40 costimulatory receptor to improve virotherapy efficacy in diffuse midline gliomas

  • Cell Rep Med. 2025 Jul 15;6(7):102204. doi: 10.1016/j.xcrm.2025.102204.
Sara Labiano  1 ,  Javier Marco-Sanz  2 ,  Iker Ausejo-Mauleon  2 ,  Virginia Laspidea  2 ,  Reyes Hernández-Osuna  2 ,  Marc Garcia-Moure  2 ,  Daniel de la Nava  2 ,  Sara Nuin  2 ,  Marisol Gonzalez-Huarriz  2 ,  Timothy N Phoenix  3 ,  Ibon Tamayo  4 ,  Marta Zalacain  2 ,  Andrea Lacalle  2 ,  Lucía Marrodan  2 ,  Montserrat Puigdelloses  2 ,  Irati Hervás-Corpión  2 ,  Maria C Ochoa  2 ,  Noelia Casares  2 ,  Oren J Becher  5 ,  Candelaria Gomez-Manzano  6 ,  Juan Fueyo  6 ,  Jaime Gallego Perez-Larraya  2 ,  Ana Patiño-Garcia  2 ,  Marta M Alonso  7
Affiliations
  • 1. Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. Electronic address: [email protected].
  • 2. Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain.
  • 3. Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
  • 4. Bioinformatics Platform, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
  • 5. Jack Martin Fund Division of Pediatric Hematology-oncology, Mount Sinai, New York, NY, USA.
  • 6. Dpt. Of NeuroOncology, UT MD Anderson Cancer Center, Houston, TX, USA.
  • 7. Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. Electronic address: [email protected].
PMID: 40578365 DOI: 10.1016/j.xcrm.2025.102204
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; DIPG; DMG; Delta-24-RGD; dendritic cells; diffuse intrinsic pontine glioma; diffuse midline glioma; oncolytic adenovirus.
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