【摘要】 目的：探索不同放疗方式与嵌合抗原受体T(CAR-T)细胞协同治疗大肿块型淋巴瘤的疗效。方法：建立大肿块型淋巴瘤异种移植小鼠模型，使用低、中、高剂量的X射线对小鼠进行照射，测量照射后各组小鼠肿瘤体积的变化情况。再将低、中、高剂量的X射线分别与CAR-T细胞联用对小鼠进行治疗，记录不同的联用方式治疗后肿瘤体积的变化情况和各组小鼠的生存时间，使用流式细胞术检测各组小鼠外周血和肿瘤内CAR-T细胞占比的差异，观察治疗后各组小鼠的不良反应。结果：单纯X射线治疗无法控制巨块型淋巴瘤小鼠的肿瘤进展，而分别将低、中、高剂量的X射线与CAR-T细胞联用则均能使小鼠的肿瘤体积缩小。与低剂量联合组相比，中、高剂量联合组小鼠的肿瘤体积缩小更显著且未见重新增大的迹象（F组间=1 052.364,F时间=14 861.095,F交互=49.864，均P<0.001；组间均P<0.05），此外，中剂量联合组[HR=21.880(3.884～124.600),Log-rankχ~2=12.090,P<0.01]和高剂量联合组[HR=21.880(3.884～124.600),Log-rankχ~2=12.090,P<0.01]小鼠生存期也均明显延长。中、高剂量X射线可能更利于CAR-T细胞的瘤内浸润，与低剂量联合组相比，中（t=28.200,P<0.05）、高（t=23.960,P<0.05）剂量联合组在治疗后第14天的瘤内CAR-T细胞比例均明显增加。不同联用方式的不良反应大多在可耐受范围内。结论：与低剂量X射线相比，中、高剂量X射线能与CD19 CAR-T细胞协同更有效地治疗大肿块型淋巴瘤。更多还原

【Abstract】 Objective:To explore the efficacy of different radiotherapy modalities in synergistic treatment of bulky lymphoma with chimeric antigen receptor T(CAR-T)cells.Methods:The bulky lymphoma xenograft mice models were established,which were irradiated with low,medium and high doses of X-rays. The changes in the tumor volume of the mice in each group were measured after irradiation. After that,the low,medium and high doses of X-rays were combined with CAR-T cells to treat the mice,and the changes in tumor volume and the survival time of those mice in each group were recorded after different combination treatments. Flow cytometry was used to detect the differences in the percentage of CAR-T cells in the peripheral blood and tumors of the mice in each group,and the adverse reactions of the mice in each group were observed after treatment.Results:X-ray treatment alone was unable to control tumor progression in mice with bulky lymphoma,whereas combining low,medium,and high doses of X-rays with CAR-T cells,respectively,all resulted in a reduction in tumor size. Compared with the low-dose combination group,mice in the medium-and high-dose combination groups showed more significant reduction in tumor volume,which showed no signs of re-enlargement,either(Fbetween groups=1 052.364,Ftime=14 861.095,Finteraction=49.864,allP<0.001;P<0.05 for all between groups). In addition,the survival period of mice in the medium-dose combination group[HR=21.880(3.884-124.600),Log-rankχ~2=12.090,P<0.01] and high-dose combination group[HR=21.880(3.884-124.600),Log-rankχ~2=12.090,P<0.01] were also significantly prolonged. Medium-and high-dose X-rays might be more favorable for intratumoral infiltration of CAR-T cells. The proportion of intratumoral CAR-T cells was significantly increased in both the medium(t=28.200,P<0.05)and high(t=23.960,P<0.05)dose combination groups on day 14 post-treatment compared to the low-dose combination group. Most of the adverse effects of the different combination modalities were within the tolerable range.Conclusion:Compared to low-dose X-rays,medium-and high-dose X-rays can synergize with CD19 CAR-T cell therapy to more effectively treat bulky lymphoma.更多还原