成纤维细胞激活蛋白 (FAP) 是一种新兴的治疗诊断靶点，在癌症相关成纤维细胞和包括肉瘤在内的某些肿瘤细胞上高表达。我们研究了 [225Ac]Ac-FAPI-46 作为单一疗法或与免疫检查点阻断 (ICB) 联合疗法在对 ICB 敏感或耐药的免疫活性小鼠肉瘤模型中的抗肿瘤功效。[68Ga]Ga- 和 [225Ac]Ac -在带有C3H/Sed/Kam小鼠的皮下FAP FSA纤维肉瘤中测试FAPI-46。作为单一疗法以及与抗 PD-1 抗体联合使用，最多三个周期的 60 kBq [225Ac]Ac-FAPI-46 的疗效进行了评估。 [225Ac]Ac-FAPI-46 和/或 ICB 在 FAP 过表达 FSA (FSA-F) 肿瘤中的疗效进一步比较，这些肿瘤对 ICB 敏感或在阿巴西普存在下通过肿瘤诱导而呈现 ICB 耐药性。[225Ac] ]Ac-FAPI-46 在高达 3 × 60 kBq 时具有良好的耐受性，但对 FSA 肿瘤生长的影响很小。三个周期的[225Ac]Ac-FAPI-46 和 ICB 的组合导致 55% (6/11) 的小鼠生长延迟，18% (2/11) 的小鼠肿瘤部分消退。在 FAP 过度表达的 FSA-F 肿瘤中，[225Ac]Ac-FAPI-46 和 ICB 均有效，且联合用药没有额外益处。然而，在局部免疫抑制和 ICB 耐药的 FAP-F 肿瘤中，[225Ac]Ac-FAPI-46 恢复了对 ICB 的反应性，导致联合组中 56% 的小鼠肿瘤显着消退，并在术后 60 天无肿瘤生存[225Ac]Ac-FAPI-46 功效与肿瘤 FAP 表达水平相关，并且可以恢复对 PD-1 ICB 的反应性。这些数据表明，根据靶标表达仔细选择患者并合理设计联合疗法对于最大限度地发挥 FAP 靶向放射配体的治疗效果至关重要。© 2024。作者。

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 [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB.[68Ga]Ga- and [225Ac]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 [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]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.[225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]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 [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]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.[225Ac]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.© 2024. The Author(s).