Evaluating [²²⁵Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice

Area of Science:

• Oncology
• Radiopharmaceutical Therapy
• Immunotherapy

Background:

• Fibroblast Activation Protein (FAP) is a key target in cancer-associated fibroblasts and certain tumors like sarcoma.
• Theranostic applications of FAP-targeting agents are emerging for cancer treatment.

Purpose of the Study:

• To evaluate the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy and in combination with immune checkpoint blockade (ICB).
• To assess efficacy in immunocompetent murine sarcoma models, including those sensitive and resistant to ICB.

Main Methods:

• [225Ac]Ac-FAPI-46 was administered in up to three cycles (60 kBq) to mice bearing FAP+ fibrosarcoma.
• Efficacy was tested as monotherapy and combined with anti-PD-1 antibody.
• Studies included ICB-sensitive and ICB-resistant FAP-overexpressing tumors.

Main Results:

• [225Ac]Ac-FAPI-46 monotherapy showed minimal effect on tumor growth.
• Combination therapy with [225Ac]Ac-FAPI-46 and ICB led to growth delay (55%) and partial regression (18%) in sensitive models.
• In ICB-resistant, immunosuppressed tumors, [225Ac]Ac-FAPI-46 restored ICB sensitivity, achieving significant regression and 56% tumor-free survival.

Conclusions:

• The efficacy of [225Ac]Ac-FAPI-46 correlates with tumor FAP expression.
• [225Ac]Ac-FAPI-46 can re-sensitize tumors to PD-1 immune checkpoint blockade.
• Patient selection based on FAP expression and combination strategies are crucial for maximizing FAP-targeting radioligand therapy.