Page 28 - ARNM-1-2

Advances in Radiotherapy
& Nuclear Medicine FAP-targeted RLT in cancer

who reported a case involving a patient with last-stage weakening the patient’s immune response against the
breast cancer bone metastasis, treated with Y-labeled tumor. Furthermore, CAFs produce ECM within the TME.
90
FAPI-04. Following treatment with 2.9 GBq Y-FAPI-04, The ECM forms a tissue structure that supports tumor
90
the patients experienced symptom improvement with no growth and migration. ECM remodeling may restrict
signs of toxicity . Another notable case was presented the infiltration and activity of immune cells, thereby
[11]
by Ballal et al., where Lu-DOTA.SA.FAPi radionuclide reducing the tumor’s visibility to the immune system .
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[57]
therapy was administered to an end-stage breast cancer Consequently, immune cells encounter greater difficulty
patient (a single cycle of 3.2 GBq). This treatment reduced reaching the tumor area, compromising the efficacy of
symptom intensity without any treatment-related adverse immunotherapy.
events . At the 18-month mark following TRT, Fendler Numerous ongoing clinical trials investigating non-
[13]
et al. conducted a follow-up study on patients who radionuclide-targeting CAF/FAP therapies have proposed
had undergone FAP-targeted RLT, monitored through combinations of therapeutic approaches (Table 1). These
FDG PET/CT scans. Disease status was assessed based
on the RECIST/PERCIST criteria. The results revealed studies have explored the simultaneous use of multiple
that patients who exhibited a partial response or had strategies to improve therapeutic outcomes. The findings
stable disease following Y-FAPI-46 therapy exhibited from these clinical trials hold the potential to revolutionize
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a significantly longer median survival than those with the management of advanced tumors. However, as of yet,
[49]
progressive disease (14.4 vs. 6.6 months) . While none no clinical trials have reported promising results. One
of the patients achieved a complete response following possible reason for this lack of success may be the limited
FAP-targeted RLT, promising results have been reported efficacy of non-radionuclide-targeting CAF/FAP therapy,
in the literature. Notably, this therapy has shown a which could impede its ability to synergize effectively with
generally favorable safety profile, with minimal toxicity other treatment modalities in combination therapy.
and no reported allergic reactions. Several studies have External beam radiation therapy (EBRT) is among the
identified grades 3 and 4 hematological and hepatobiliary most extensively used therapeutic modalities in clinical
toxicities [47-49] . The interpretation of these toxicities should tumor management . EBRT represents a standard and
[58]
be approached cautiously, considering the inclusion of effective treatment approach for various types of cancers,
heavily pre-treated patients with metastases. Nevertheless, with the goal of precisely targeting and eliminating cancer
repeat therapy is feasible and safe. Figure 2 shows PET and cells using high-precision radiation while minimizing
single-photon emission computed tomography (SPECT) damage to surrounding healthy tissues . EBRT can induce
[59]
images of a 25-year-old man with known nasopharyngeal double-stranded DNA breaks, which exhibit lower repair
carcinoma (NPC) who received experimental therapy with rates and do not rely on oxygen availability. Previous
3.7 GBq of Lu-FAPI-46. studies have demonstrated that both EBRT and TRT can
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induce DNA damage, triggering the upregulation of pro-
6. FAP-targeted RLT combined with inflammatory cytokines, including interferons, through
immunotherapy for a synergistic effect the activation of the stimulator of the interferon genes

[60]
Cancer immunotherapy, specifically the use of immune (STING) pathway . These cytokines play a pivotal role in
checkpoint inhibitors (ICIs) targeting programmed cell attracting immunostimulatory immune cells to the TME,
death 1 (PD-1)/programmed cell death ligand 1 (PD-L1), such as T cells, antigen-presenting cells, and natural killer
[61]
has firmly established itself as a fundamental approach in cells . Simultaneously, they can hinder the activity of
the fight against cancer . ICIs have significantly improved immunosuppressive immune cells, including regulatory
[52]
[62]
survival rates across various cancer types and are regarded T cells . At present, there is substantial pre-clinical and
as a significant advancement in cancer treatment . clinical evidence showing that EBRT can enhance the
[53]
Nevertheless, the clinical efficacy of ICIs is hindered response of both immunologically “hot” and “cold” tumors
by intrinsic and acquired tumor resistance, restricting to anti-PD-1 and anti-cytotoxic T lymphocyte-associated
[63]
their widespread application in cancer treatment . protein 4 (anti-CTLA-4) immune checkpoint inhibition .
[54]
Resistance to ICIs is partly attributed to the presence The combination of EBRT and immunotherapy exhibits
of immunosuppressive cells within the TME, including a synergistic antitumor effect . For many patients with
[63]
CAFs expressing FAP . CAFs can secrete various metastatic cancer, providing low-dose immune-modulating
[55]
immunosuppressive factors, such as TGF-β and IL-10, radiation therapy to all tumors using EBRT is not feasible.
which have the potential to inhibit the activity of immune This is due to the inability to target radiographically
cells and limit their ability to target tumors . These occult sites, along with the toxicity associated with large-
[56]
factors can suppress the effectiveness of immunotherapy, field or whole-body radiation, lymphocyte depletion, and
Volume 1 Issue 2 (2023) 7 https://doi.org/10.36922/arnm.1667