[153Sm]Samarium-labeled FAPI-46 radioligand therapy in a patient with lung metastases of a sarcoma

Fibroblast activation protein is overexpressed by cancerassociated fibroblasts (CAFs) in the stroma of several tumor entities and provides anti-immunogenic effects [1]. It can be targeted with radiolabeled small-molecule inhibitors (FAPIs) [2]. This image demonstrates a patient with progression of lung metastatic, fibrous spindle cell soft tissue sarcoma. Primary tumor located between bladder and rectum as well as early generations of oligo-focal metastases had previously been treated by resection and external-beam radiotherapy. In syst em i c s t a g e , mu t anom-ba s ed vac c i n a t i on [3 ] , cyclophosphamide, and pazopanib had already been used but the patient was considered inappropriate for standard chemotherapy with anthracyclines. An interdisciplinary tumor conference considered experimental FAPI-RLT a promising option for this therapy-refractory patient to serve as a “can opener” for succeeding immunotherapy. FAPI-PET/CT demonstrated target positive tumor phenotype (a). Due to the relatively short biological tumor halflife of quinoline-based FAPI-46 [1], it was labeled with short physical half-life (46.3 h) Sm. Emission scans during therapy demonstrate tumor targeting up to 44 h p.i. and rapid clearance from normal organs (b). Three cycles with cumulative 20 GBq Smand 8GBq Y-90-FAPI-46 (Sm was not available with sufficiently high specific activity) were well tolerated and achieved stable disease for 8 months (c). Next treatment lines were pembrolizumab, experimentally enhanced with oncolytic parvovirus [4], and nab-paclitaxel. Under both therapies, the patient progressed after only 3 months. One explanation for the clinical activity of Y/SmFAPI-46 in this particular case might be FAP expression in both CAFs and sarcoma tumor cells [5], which is unfortunately not the case in other tumor entities. Of course, one case is no proof of general efficacy but obviously this image encourages further studies of FAPI-RLT against soft tissue sarcoma. However, due to technical issues related to Sm, e.g., regarding specific activity and contamination with Eu, additional short physical half-life isotopes should be evaluated as alternative options. This article is part of the Topical Collection on Image of the month


Image of the month
Fibroblast activation protein is overexpressed by cancerassociated fibroblasts (CAFs) in the stroma of several tumor entities and provides anti-immunogenic effects [1]. It can be targeted with radiolabeled small-molecule inhibitors (FAPIs) [2].
This image demonstrates a patient with progression of lung metastatic, fibrous spindle cell soft tissue sarcoma. Primary tumor located between bladder and rectum as well as early generations of oligo-focal metastases had previously been treated by resection and external-beam radiotherapy. In syst e m i c s t a g e , m u t a n o m -b a s e d v a c c i n a t i o n [ 3 ] , cyclophosphamide, and pazopanib had already been used but the patient was considered inappropriate for standard chemotherapy with anthracyclines. An interdisciplinary tumor conference considered experimental FAPI-RLT a promising option for this therapy-refractory patient to serve as a "can opener" for succeeding immunotherapy.
FAPI-PET/CT demonstrated target positive tumor phenotype (a). Due to the relatively short biological tumor halflife of quinoline-based FAPI-46 [1], it was labeled with short physical half-life (46.3 h) 153 Sm. Emission scans during therapy demonstrate tumor targeting up to 44 h p.i. and rapid clearance from normal organs (b). Three cycles with cumulative 20 GBq 153 Sm-and 8GBq Y-90-FAPI-46 ( 153 Sm was not available with sufficiently high specific activity) were well tolerated and achieved stable disease for 8 months (c). Next treatment lines were pembrolizumab, experimentally enhanced with oncolytic parvovirus [4], and nab-paclitaxel. Under both therapies, the patient progressed after only 3 months.
One explanation for the clinical activity of 90 Y/ 153 Sm-FAPI-46 in this particular case might be FAP expression in both CAFs and sarcoma tumor cells [5], which is unfortunately not the case in other tumor entities. Of course, one case is no proof of general efficacy but obviously this image encourages further studies of FAPI-RLT against soft tissue sarcoma. However, due to technical issues related to 153 Sm, e.g., regarding specific activity and contamination with 154 Eu, additional short physical half-life isotopes should be evaluated as alternative options.
Funding Open Access funding enabled and organized by Projekt DEAL.

Declarations
Conflict of interest TL, UH, CK, and FLG have a patent application for FAPI-ligands. TL, UH, CK, and FLG also hold shares of a consultancy for iTheranostics.
Ethics approval This image presents a case report from clinical practice and does not require IRB approval or registration as a clinical trial.
Consent to participate/consent for publication Patient gave written informed consent to receive experimental therapy and anonymized publication of this case.
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