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

Purpose Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [ 225 Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint...

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Veröffentlicht in:European journal of nuclear medicine and molecular imaging 2024-11, Vol.51 (13), p.4026-4037
Hauptverfasser: Taddio, Marco F., Doshi, Suraj, Masri, Marwan, Jeanjean, Pauline, Hikmat, Firas, Gerlach, Alana, Nyiranshuti, Lea, Rosser, Ethan W., Schaue, Dorthe, Besserer-Offroy, Elie, Carlucci, Giuseppe, Radu, Caius G., Czernin, Johannes, Lückerath, Katharina, Mona, Christine E.
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Zusammenfassung:Purpose Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [ 225 Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. Methods [ 68 Ga]Ga- and [ 225 Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [ 225 Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [ 225 Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. Results [ 225 Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [ 225 Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [ 225 Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [ 225 Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. Conclusion [ 225 Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.
ISSN:1619-7070
1619-7089
DOI:10.1007/s00259-024-06809-4