Preclinical Evaluation of Radium-223 and Immune Checkpoint Inhibitors Using an Immune-Competent Model of Prostate...

Area of Science:

• Oncology
• Radiopharmaceutical Therapy
• Immunotherapy

Background:

• Radium-223 dichloride (223RaCl2) is an alpha-emitting radiopharmaceutical approved for bone metastases in metastatic castration-resistant prostate cancer (mCRPC).
• Combining 223RaCl2 with immune checkpoint inhibitors (ICIs) may enhance therapeutic outcomes by leveraging both targeted radiation and immune system activation.

Purpose of the Study:

• To investigate the therapeutic and immunological effects of combining 223RaCl2 with ICIs in a murine model of prostate cancer bone metastasis.
• To assess the impact of 223RaCl2 dose escalation and combination therapy on tumor growth, survival, and immune infiltration.

Main Methods:

• Established bone metastases in immunocompetent mice using luciferase-expressing MyC-CaP cells.
• Administered escalating doses of 223RaCl2 alone or in combination with anti-CTLA-4 and anti-PD-L1 ICIs.
• Monitored tumor growth via bioluminescence imaging and assessed bone remodeling, radiopharmaceutical distribution, immune infiltration, and gene expression using various imaging and molecular techniques.

Main Results:

• 223RaCl2 alone did not significantly inhibit tumor growth or improve survival.
• Biodistribution studies revealed preferential localization of 223RaCl2 to tumor-adjacent bone, with minimal uptake in tumor tissue.
• Combination therapy did not enhance tumor control or immune infiltration compared to monotherapy, although Mhc1 was upregulated in the combination group.

Conclusions:

• 223RaCl2's primary localization to bone surfaces limits its direct cytotoxic and immunomodulatory effects within the tumor microenvironment.
• While combination with ICIs did not improve efficacy in this model, the findings support further research into spatially targeted alpha therapies to potentiate immunotherapy for mCRPC.