Berg-Larsen Axel, Mobergslien Anne, Moen Ingrid, Petros Gebregziabher, Kristian Alexander, Gunvaldsen Kristine Sponheim, Cruciani Véronique, Wickstroem Katrine, Bjerke Roger Malerbakken, Karlsson Jenny, Cuthbertson Alan
Bayer AS, Oslo, Norway.
Front Med (Lausanne). 2022 Nov 15;9:1033303. doi: 10.3389/fmed.2022.1033303. eCollection 2022.
Targeted thorium-227 conjugates comprise the combination of a monoclonal antibody with specificity for a tumor cell antigen and a 3,2-HOPO chelator enabling complexation of thorium-227 (Th-227). The radiolabeled conjugate functions as an effective delivery system of alpha-particle radiation to the surface of the tumor cell inducing difficult to repair complex DNA damage and cell death. In addition, the mechanism of action of targeted alpha therapy (TAT) appears to involve a significant component linked to stimulation of the immune system. We report herein evidence of immune activation and long-lasting immune protection of a TAT in a syngeneic model using the MC-38 murine cell line. Firstly, MC-38 cells were irradiated with the thorium labeled antibody before subcutaneous implantation into mice. These mice were then rechallenged with MC-38 cells contra-laterally. In the group receiving irradiated cells, 9 out of 10 animals had no measurable tumor growth compared to aggressive tumor growth in the control group. Secondly, in an efficacy study, 500 kBq/kg of thorium labeled antibody alone or in combination with PD-1 checkpoint inhibitor gave statistically significant tumor growth inhibition compared to vehicle control. Animals with no measurable tumors were once again rechallenged contra-laterally with MC-38 cells. The re-growth of tumors was significantly delayed (approx. 60 days) in the treatment group compared to age-matched controls (approx. 30 days) in the monotherapy group. Interestingly, in the TAT/ PD-1 combination group no re-growth was observed demonstrating the potential of combining a TAT with checkpoint inhibition therapy. Finally, tumors were excised from treated mice and analyzed by flow cytometry and immunohistochemistry (IHC). Analysis revealed significant infiltration of CD8+ T-cells and mature dendritic cells compared to vehicle controls. Together these results indicated that an ongoing immune response from treatment with alpha radiation could be enhanced by check-point inhibition.
靶向钍-227偶联物由对肿瘤细胞抗原具有特异性的单克隆抗体与能够使钍-227（Th-227）络合的3,2-HOPO螯合剂组成。放射性标记的偶联物作为α粒子辐射的有效递送系统，作用于肿瘤细胞表面，诱导难以修复的复杂DNA损伤和细胞死亡。此外，靶向α治疗（TAT）的作用机制似乎涉及与免疫系统刺激相关的重要成分。我们在此报告了在同基因模型中使用MC-38小鼠细胞系的TAT免疫激活和长期免疫保护的证据。首先，将钍标记的抗体照射MC-38细胞，然后皮下植入小鼠体内。然后对这些小鼠的对侧再次接种MC-38细胞。在接受照射细胞的组中，10只动物中有9只没有可测量的肿瘤生长，而对照组中肿瘤生长旺盛。其次，在一项疗效研究中，与载体对照相比，单独使用500 kBq/kg的钍标记抗体或与PD-1检查点抑制剂联合使用均产生了具有统计学意义的肿瘤生长抑制。无可测量肿瘤的动物再次在对侧接种MC-38细胞。与单药治疗组的年龄匹配对照组（约30天）相比，治疗组的肿瘤再生长明显延迟（约60天）。有趣的是，在TAT/PD-1联合组中未观察到肿瘤再生长，这表明TAT与检查点抑制疗法联合的潜力。最后，从治疗的小鼠中切除肿瘤，并通过流式细胞术和免疫组织化学（IHC）进行分析。分析显示，与载体对照相比，CD8 + T细胞和成熟树突状细胞有明显浸润。这些结果共同表明，通过检查点抑制可以增强α辐射治疗引起的持续免疫反应。
