1,090 Publications and 5 Years Later: Is FAP-Targeted Theranostics Really Happening?

FAP LIGANDS FOR DIAGNOSIS

To develop FAP-specific inhibitors, Jansen et al. (6,7) examined a variety of structurally related small molecules, with some of them being highly specific for FAP. These molecules were used as lead structures for new radiopharmaceuticals and as lead structures for the development of FAP inhibitors (FAPIs) for diagnosis and potential therapy (8,9). These structures created a substantial interest in their use for imaging of diseases that show an activation of fibroblasts such as in tumors and cardiac, rheumatologic, and fibrotic diseases and an incentive for developing similar or new small-molecule inhibitors or peptidic ligands that bind to FAP. Imaging studies showed that FAP ligands can be used as pan-tumor tracers (10,11). In the meantime, many studies comparing FAPIs and FDG revealed a better diagnostic performance for the FAP-targeting agents (11–14). Besides its application in tumors, a favorable outcome was also seen in diseases with tissue remodeling activity such as rheumatologic and cardiologic diseases, among others (15–17).

THERAPIES TARGETING FAP-EXPRESSING FIBROBLASTS

Several approaches have been used to treat tumors by targeting FAP: immunoconjugates, CAR T cells, tumor immunotherapy, vaccines, peptide–drug complexes, FAPI, and antibodies (2,18–20). Many of these approaches showed promising results in preclinical studies, but these positive effects could not be seen in clinical applications (20).

FAP-targeting strategies were shown to be more effective when combined with other treatment modalities such as chemotherapy, vaccination, or antibodies (2,21,22). This may be an approach to address the lack of efficacy observed with the antibody sibrotuzumab (20).

With respect to isotope-based therapies using FAP-targeting agents, the available data are limited at this stage. Hamacher et al. (23) treated 11 patients with solitary fibrous tumors who were shown in PET imaging to have increased FAP mRNA content and high FAPI uptake. The patients received a total of 34 cycles (median, 3 cycles each) of ⁹⁰Y-FAPI-46, resulting in disease control in 9 patients (82%) and a median progression-free survival of 227 d. The same group treated patients with advanced sarcoma (16), pancreatic cancer (3), prostate cancer (1), and stomach cancer (1) with up to 4 cycles of ⁹⁰Y-FAPI-46 (24). They observed disease control in 8 of 21 patients: 1 partial response and 7 stable disease after radiopharmaceutical therapy. Disease control was associated with prolonged overall survival (P = 0.013). Dosimetry was acquired in 19 (90%) patients. The mean absorbed dose was 0.53 Gy/GBq in the kidneys, 0.04 Gy/GBq in the bone marrow, and less than 0.14 Gy/GBq in the liver and lungs. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients, with thrombocytopenia (n = 6) and anemia (n = 6) being the most prevalent.

A retrospective analysis assessed the safety and efficacy of [¹⁷⁷Lu]-DOTAGA-FAPI dimer therapy in 16 patients with advanced breast cancer (25). Monitoring with [⁶⁸Ga]-DOTA.SA.FAPI PET/CT revealed a partial response in 25% of patients and disease progression in 37.5% of patients. According to the VAS response criteria, 26.3% of patients achieved complete response, 15.7% had partial response, 42% showed minimal response, 11% had stable disease, and 5% had no response. At the time of the analysis, the median overall survival was 12 mo, and the median progression-free survival was 8.5 mo. Notably, no severe hematologic, renal, or hepatic toxicities, electrolyte imbalances, or adverse events of grade 3 or 4 were observed during the study. Baum et al. (26) used the FAP-targeting peptide ¹⁷⁷Lu-FAP-2286 for the treatment of 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary. In these patients, no grade 4 adverse events were observed, whereas grade 3 events occurred in 3 patients: 1 with pancytopenia, 1 with leukocytopenia, and 1 with pain flare-up. Three patients reported a pain response. The doses obtained in bone metastases were 3.0 ± 2.7 Gy/GBq (range, 0.5–10.6 Gy/GBq).

In summary, isotope-based therapies delivered at the present stage do not entirely provide convincing results concerning therapy response or stable disease. It seems that tumors with a high fibrous reaction or tumors with an inherent expression of FAP on tumor cells such as sarcoma or ovarian cancer (27,28) may be better candidates than others. Furthermore, attempts to improve the performance of isotope-based methods may be followed, such as enhancement of tracer uptake, prolongation of the retention time in tumor lesions, or the use of isotopes with the goal to adjust the physical half-life of the isotope to the biologic half-life of the carrier molecule. In this respect, molecules with a shorter biologic half-life, such as members of the FAPI family, would benefit more from isotopes such as ⁹⁰Y, ²¹²Pb, or ²¹³Bi, and ligands with a longer biologic half-life such as dimers or peptides may be combined with ¹⁷⁷Lu or ²²⁵Ac. However, the limited data available at this stage allow only premature conclusions about the therapeutic potential of FAP-directed endoradiotherapy. At present, several studies are planned or initiated: NCT04939610 (LuMIERE) and NCT05432193 (FRONTIER) in the United States and Canada and NCT04849247, NCT06081322, NCT05410821, NCT06197139, NCT06211647, and NCT05723640 in China and Singapore, which may give further insights.

YOU NEVER TREAT ALONE

In view of the outcome of FAP-directed therapy with nonradiolabeled drugs, the performance of isotope-based therapies is not surprising. This is related to the basic problem indicated at the beginning of this article: tumor heterogeneity. We are facing here 2 types of heterogeneity: first, FAP is expressed predominantly in the stroma in many tumor entities and not by the tumor cells. Only a few tumor entities such as sarcomas, mesotheliomas, and perhaps ovarian cancer and some others also show FAP-positive tumor cells. Second, there is heterogeneity of FAP expression of the stromal cells. As mentioned above, because of the heterogeneity of their origin, CAFs also show heterogeneity of their proteome. Both heterogeneities may cause an inhomogeneous dose distribution in the tumor.

How can we address that problem? To homogenize the dose in the tumor, we may engage in the design of heterodimers. This has been done using FAPI-RGD heterodimers (29,30) for imaging purposes. In these reports, the heterodimers showed a higher tracer uptake than with FDG or a FAPI monomer.

This could be extended to other combinations than a ligand for the α_vβ₃ integrin, as has been shown for a heterodimer consisting of FAPI04 and a prostate-specific membrane antigen ligand (31). In general, FAP ligands can be seen as ideal partners for heterodimers with a variety of tumor cell–targeting ligands, if available. In principle, this approach does not depend on heterodimers. Instead, cocktails consisting of 2 or more ligands could also be used.

Another option is a combination therapy consisting of isotope-based and nonisotope therapies. Since CAFs influence a variety of biologic processes such as tumor stimulation via transforming growth factor β, chemoresistance, immunosuppression, angiogenesis, metabolic collaboration, and tissue remodeling leading to increased stiffness with stimulation of mechanoreceptors followed by second messenger signaling, a variety of options are available. Since CAFs are involved in the immune suppression of tumors with an influence on immune checkpoint therapy (32,33), conferring chemoresistance and stimulating angiogenesis, endoradiotherapy with FAP ligands could be used as an enabling procedure for immunotherapy, chemotherapy, and antiangiogenic therapy.

DISCLOSURE

Uwe Haberkorn, Clemens Kratochwil, and Frederik Giesel have a patent application for quinolone-based FAP-targeting agents for imaging and therapy in nuclear medicine. Uwe Haberkorn, Clemens Kratochwil, and Frederik Giesel also have shares of a consultancy group for iTheranostics. Frederik Giesel is advisor at ABX, SOFIE Biosciences, α-Fusion, and Telix Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.