Zhang Yujun, Deshane Jessy S, Yang Eddy S, Larimer Benjamin
Graduate Biomedical Sciences, The University of Alabama at Birmingham, Birmingham, Alabama; Department of Radiology, The University of Alabama at Birmingham, Birmingham, Alabama.
Division of Pulmonary Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama.
Int J Radiat Oncol Biol Phys. 2024 Apr 1;118(5):1217-1227. doi: 10.1016/j.ijrobp.2023.12.047. Epub 2024 Jan 9.
This study aimed to provide a novel noninvasive method to quantify abscopal immune activation and predict combinational treatment response using [Ga]-NOTA-GZP positron emission tomography (PET) imaging.
4T1 breast cancer cells were implanted bilaterally in the mammary fat pad of Balb/c mice and Lewis's lung cancer cells (LLC) were implanted bilaterally on the shoulders of C57/Bl6 mice. One of the tumors received a single fraction of 12 Gy irradiation followed by combination of concurrent PD-1 and CTLA-4 inhibitors or controls. Tumor growth of the irradiated and nonirradiated tumors was measured and compared with 12 Gy irradiation only, checkpoint inhibitor only, and no treatment control group. Changes in granzyme B activity were assessed with [Ga]-NOTA-GZP PET imaging from baseline and every 3 days until day 9.
In the 4T1 model, concurrent treatment with dual checkpoint inhibitors and radiation resulted in reduction of the irradiated tumor volume at day 30. At this same time point, the nonirradiated tumor volume for combination treatment decreased significantly, consistent with abscopal immune activation. Similarly, in the LLC model, concurrent treatment inhibited tumor growth on the nonirradiated tumor at day 15. On day 9, granzyme B PET signal in both 4T1 and LLC models was significantly higher in the nonirradiated tumors that responded to concurrent treatment compared with subsequent nonresponding tumors. A similar lack of granzyme B signal was observed in the nonirradiated tumors from mice that received radiation or checkpoint inhibitors only and control tumors. Receiver operating characteristic analysis identified a PET threshold of 1.505 and 1.233 on day 9 that predicted treatment response in 4T1 and LLC models, respectively.
[Ga]-NOTA-GZP PET imaging was able to noninvasively predict abscopal immune activation before subsequent tumor volume changes after combination treatment. It provides a potential translational paradigm for investigating distal immune activation postradiation in a clinical setting.
本研究旨在提供一种新型非侵入性方法，用于定量远隔效应免疫激活，并使用[镓]-NOTA-GZP正电子发射断层扫描（PET）成像预测联合治疗反应。
将4T1乳腺癌细胞双侧植入Balb/c小鼠的乳腺脂肪垫，将刘易斯肺癌细胞（LLC）双侧植入C57/Bl6小鼠的肩部。其中一个肿瘤接受单次12 Gy照射，随后联合使用PD-1和CTLA-4抑制剂或对照。测量照射和未照射肿瘤的生长情况，并与仅接受12 Gy照射、仅使用检查点抑制剂以及未治疗的对照组进行比较。从基线开始，每3天直至第9天，使用[镓]-NOTA-GZP PET成像评估颗粒酶B活性的变化。
在4T1模型中，联合使用双检查点抑制剂和放疗可使第30天照射肿瘤的体积减小。在同一时间点，联合治疗组未照射肿瘤的体积显著减小，这与远隔效应免疫激活一致。同样，在LLC模型中，联合治疗在第15天抑制了未照射肿瘤的生长。在第9天，与随后无反应的肿瘤相比，4T1和LLC模型中对联合治疗有反应的未照射肿瘤的颗粒酶B PET信号显著更高。在仅接受放疗或检查点抑制剂的小鼠的未照射肿瘤以及对照肿瘤中，观察到类似的颗粒酶B信号缺失。受试者操作特征分析确定，第9天PET阈值分别为1.505和1.233时，可分别预测4T1和LLC模型中的治疗反应。
[镓]-NOTA-GZP PET成像能够在联合治疗后肿瘤体积发生后续变化之前，非侵入性地预测远隔效应免疫激活。它为在临床环境中研究放疗后远端免疫激活提供了一种潜在的转化范例。
