Radionuclide-Dependent Stimulation of Antitumor Immunity in GD2-Targeted Radiopharmaceutical Therapy Combined with...

Area of Science:

• Oncology
• Immunotherapy
• Radiochemistry

Background:

• Radiopharmaceutical therapy (RPT) delivers targeted radiation and shows potential for combination with immune checkpoint inhibitors (ICIs).
• Synergy between RPT and ICIs may be influenced by radionuclide characteristics, radiation dose, and tumor microenvironment factors.

Purpose of the Study:

• To investigate how different radionuclides and absorbed doses affect immune stimulation and therapeutic outcomes of GD2-targeted RPT combined with ICIs.
• To evaluate the impact of radionuclide selection and dose on the efficacy of anti-GD2 antibody-based RPT in combination with dual ICIs.

Main Methods:

• Dinutuximab, an anti-GD2 antibody, was radiolabeled with beta-emitters (90Y, 177Lu) or an alpha-emitter (225Ac).
• Mice with GD2+ tumors received 4 or 15 Gy absorbed doses with or without dual ICIs (anti-CTLA-4 and anti-PD-L1).
• Analyses included in vivo imaging, biodistribution, survival studies, histology, and gene expression.

Main Results:

• All radiolabeled antibodies showed tumor-specific uptake in GD2+ tumors.
• Combination therapy improved survival in a dose- and radionuclide-dependent manner, with 225Ac at 15 Gy showing the greatest benefit.
• Treatment enhanced type I interferon signaling, increased MHC-I and PD-L1 expression, and modulated T cell populations (e.g., reduced Tregs with 90Y, enhanced interferon activation with 225Ac).

Conclusions:

• Radionuclide selection and absorbed dose are critical determinants of immune and therapeutic outcomes in antibody-based RPT combined with ICIs.
• Optimizing radionuclide delivery and dose is essential for maximizing the efficacy of combination RPT and ICI strategies.