Projecten per jaar
Samenvatting
PURPOSE: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225Ac or 131I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB).
METHODS: We studied the biodistribution and tumour uptake of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [225Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [225Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB.
RESULTS: The biodistribution showed high tumour uptake of [131I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [225Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [131I]I-GMIB-4AH29 or [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [225Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy.
CONCLUSION: [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [225Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.
Originele taal-2 | English |
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Pagina's (van-tot) | 444-457 |
Aantal pagina's | 14 |
Tijdschrift | European Journal of Nuclear Medicine and Molecular Imaging |
Volume | 52 |
DOI's | |
Status | Published - jan 2025 |
Bibliografische nota
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.-
SRP83: SRP-Onderzoekszwaartepunt: Immunoregulatoire cellen als doelwit voor moleculaire beeldvorming en therapie in inflammatoire ziekten en kanker
Van Ginderachter, J., Lahoutte, T., Lahoutte, T., Van Ginderachter, J., Devoogdt, N., Raes, G., Stijlemans, B., Vincke, C. & De Groof, T.
1/11/22 → 31/10/27
Project: Fundamenteel
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BRGRD44: Joint R&D 2020: IMPACT : Verkwikkende precisie Medicijnen voor voorspellende beeldvorming van sdAb-basis anti-kanker theranostica
Lahoutte, T., Keyaerts, M., Krasniqi, A., Breckpot, K. & Goyvaerts, C.
1/07/20 → 30/06/24
Project: Toegepast