放疗、贝林妥欧单抗和免疫检查点抑制剂联合治疗可根除小鼠的晚期实体瘤和转移灶。

BACKGROUND: Current clinical trials are using radiation therapy (RT) to enhance an antitumor response elicited by high-dose interleukin (IL)-2 therapy or immune checkpoint blockade (ICB). Bempegaldesleukin (BEMPEG) is an investigational CD122-preferential IL-2 pathway agonist with prolonged in vivo half-life and preferential intratumoral expansion of T effector cells over T regulatory cells. BEMPEG has shown encouraging safety and efficacy in clinical trials when used in combination with PD-1 checkpoint blockade. In this study, we investigated the antitumor effect of local RT combined with BEMPEG in multiple immunologically 'cold' tumor models. Additionally, we asked if ICB could further enhance the local and distant antitumor effect of RT+BEMPEG in the setting of advanced solid tumors or metastatic disease. METHODS: Mice bearing flank tumors (B78 melanoma, 4T1 breast cancer, or MOC2 head and neck squamous cell carcinoma) were treated with combinations of RT and immunotherapy (including BEMPEG, high-dose IL-2, anti(α)-CTLA-4, and α-PD-L1). Mice bearing B78 flank tumors were injected intravenously with B16 melanoma cells to mimic metastatic disease and were subsequently treated with RT and/or immunotherapy. Tumor growth and survival were monitored. Peripheral T cells and tumor-infiltrating lymphocytes were assessed via flow cytometry. RESULTS: A cooperative antitumor effect was observed in all models when RT was combined with BEMPEG, and RT increased IL-2 receptor expression on peripheral T cells. This cooperative interaction was associated with increased IL-2 receptor expression on peripheral T cells following RT. In the B78 melanoma model, RT+BEMPEG resulted in complete tumor regression in the majority of mice with a single ~400 mm tumor. This antitumor response was T-cell dependent and supported by long-lasting immune memory. Adding ICB to RT+BEMPEG strengthened the antitumor response and cured the majority of mice with a single ~1000 mm B78 tumor. In models with disseminated metastasis (B78 primary with B16 metastasis, 4T1, and MOC2), the triple combination of RT, BEMPEG, and ICB significantly improved primary tumor response and survival. CONCLUSION: The combination of local RT, BEMPEG, and ICB cured mice with advanced, immunologically cold tumors and distant metastasis in a T cell-dependent manner, suggesting this triple combination warrants clinical testing.

背景：目前的临床试验正在使用放射治疗（RT）来增强大剂量白细胞介素（IL）-2 治疗或免疫检查点阻断（ICB）引起的抗肿瘤反应。贝美格莱辛（BEMPEG）是一种研究性的 CD122 优先 IL-2 途径激动剂，具有体内半衰期延长和优先在肿瘤内扩增 T 效应细胞而不是 T 调节细胞的特点。当与 PD-1 检查点阻断联合使用时，BEMPEG 在临床试验中显示出令人鼓舞的安全性和疗效。在这项研究中，我们研究了局部 RT 联合 BEMPEG 在多种免疫“冷”肿瘤模型中的抗肿瘤作用。此外，我们还研究了在晚期实体瘤或转移性疾病中，ICB 是否可以进一步增强 RT+BEMPEG 的局部和远处抗肿瘤作用。

方法：在携带侧腹肿瘤的小鼠（B78 黑色素瘤、4T1 乳腺癌或 MOC2 头颈部鳞状细胞癌）中，采用 RT 和免疫疗法（包括 BEMPEG、大剂量 IL-2、抗（α）-CTLA-4 和 α-PD-L1）联合治疗。在携带 B78 侧腹肿瘤的小鼠中静脉注射 B16 黑色素瘤细胞以模拟转移性疾病，然后用 RT 和/或免疫疗法进行治疗。监测肿瘤生长和存活情况。通过流式细胞术评估外周 T 细胞和肿瘤浸润淋巴细胞。

结果：当 RT 与 BEMPEG 联合使用时，所有模型均观察到协同抗肿瘤作用，并且 RT 增加了外周 T 细胞上的 IL-2 受体表达。这种协同相互作用与 RT 后外周 T 细胞上 IL-2 受体表达的增加有关。在 B78 黑色素瘤模型中，RT+BEMPEG 导致大多数小鼠的单个400mm 肿瘤完全消退，其中大部分小鼠。这种抗肿瘤反应是 T 细胞依赖性的，并得到持久的免疫记忆的支持。在 RT+BEMPEG 中加入 ICB 可增强抗肿瘤反应，并治愈大多数患有单个1000mm B78 肿瘤的小鼠。在具有播散性转移的模型中（B78 原发肿瘤伴 B16 转移、4T1 和 MOC2），RT、BEMPEG 和 ICB 的三联组合显著改善了原发性肿瘤的反应和存活。

结论：局部 RT、BEMPEG 和 ICB 的联合治疗在 T 细胞依赖性方式下治愈了患有晚期免疫冷肿瘤和远处转移的小鼠，表明这种三联组合值得临床测试。