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

Area of Science:

• Oncology
• Immunology
• Virology

Background:

• Diffuse midline glioma (DMG) is a highly aggressive pediatric brain tumor with limited treatment options.
• Oncolytic adenovirus Delta-24-RGD demonstrates efficacy but is not curative for DMG.
• Activating dendritic cells (DCs) via CD40 costimulation may enhance anti-tumor immunity.

Purpose of the Study:

• To investigate the efficacy and immunological impact of combining Delta-24-RGD virotherapy with CD40 agonistic antibody treatment in preclinical DMG models.
• To determine if this combination therapy can induce durable anti-tumor responses and long-term immunity.

Main Methods:

• Intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody in DMG preclinical models.
• Assessment of tumor response, survival, and immune cell infiltration.
• Mechanistic studies to elucidate the role of dendritic cells and T lymphocytes.

Main Results:

• The combination therapy was well-tolerated and induced long-term anti-tumor immunity.
• Complete responses were observed in up to 40% of preclinical DMG models.
• Therapy increased tumor-proliferating T lymphocytes, proinflammatory myeloid cells, and mature DCs with enhanced antigen uptake.
• The presence and function of cross-presenting DCs were crucial for the therapeutic effect.

Conclusions:

• Co-administration of Delta-24-RGD and anti-CD40 antibody is a promising strategy for treating diffuse midline glioma.
• This approach enhances anti-tumor immunity by modulating dendritic cells and T lymphocytes.
• Combining virotherapy with antigen-presenting cell activation offers potential for durable responses in challenging pediatric brain tumors.