Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Eur J Nucl Med Mol Imaging. 2024 Nov;51(13):4026-4037. doi: 10.1007/s00259-024-06809-4. Epub 2024 Jul 15.
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 [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.
[Ga]Ga- and [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 [Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [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.
[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 [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 [Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [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.
[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.
成纤维细胞激活蛋白（FAP）是一种新兴的治疗靶点，在癌相关成纤维细胞和某些肿瘤细胞（包括肉瘤）上高度表达。我们研究了[Ac]Ac-FAPI-46 作为单一疗法或与免疫检查点阻断（ICB）联合治疗对免疫活性的肉瘤敏感或耐药的鼠模型中的抗肿瘤疗效。
在携带 C3H/Sed/Kam 小鼠的 FAP+ FSA 纤维肉瘤的皮下部位测试了[Ga]Ga-和[Ac]Ac-FAPI-46。评估了多达三个周期的 60 kBq[Ac]Ac-FAPI-46 的单一疗法和与抗 PD-1 抗体联合治疗的疗效。还比较了 FAP 过表达的 FSA（FSA-F）肿瘤中[Ac]Ac-FAPI-46 和/或 ICB 的疗效，这些肿瘤对 ICB 敏感或在用 Abatacept 存在的情况下诱导肿瘤时对 ICB 耐药。
[Ac]Ac-FAPI-46 耐受良好，最高可达 3×60 kBq，但对 FSA 肿瘤生长的影响很小。三个周期[Ac]Ac-FAPI-46 和 ICB 的联合治疗导致 55%（6/11）的小鼠肿瘤生长延迟，18%（2/11）的小鼠出现部分肿瘤消退。在 FAP 过表达的 FSA-F 肿瘤中，[Ac]Ac-FAPI-46 和 ICB 均有效，联合治疗没有额外益处。然而，在局部免疫抑制和 ICB 耐药的 FAP-F 肿瘤中，[Ac]Ac-FAPI-46 恢复了对 ICB 的反应性，导致联合组中多达 56%的小鼠的肿瘤显著消退和无肿瘤存活，直至治疗后 60 天。
[Ac]Ac-FAPI-46 的疗效与肿瘤 FAP 表达水平相关，并能恢复对 PD-1 ICB 的反应性。这些数据表明，基于目标表达的仔细患者选择和合理设计的联合治疗方案对于最大限度地发挥 FAP 靶向放射性配体的治疗效果至关重要。
