Targeting the CD40 Co-stimulatory receptor to improve virotherapy efficacy in diffuse midline gliomas

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 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 showed that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induced 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 dendritic cells with superior tumor antigen uptake capacity. Moreover, the lack of cross-priming DCs and the prevention of DCs recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-tumor effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors. RNA-seq profiling of XFM-bearing mice tumors at day 6 treated with IgG, anti-CD40, adenovirus Delta24-RGD or the combination of anti-CD40+DElta24-RGD.