摘要
背景当前化疗联合免疫治疗广泛应用于各种类型肿瘤的治疗,但二者联合应用的最佳时序尚无定论。目的优化卡铂与PD-1免疫检查点抑制剂联合应用的顺序及间隔时间,使该联合治疗方案对免疫细胞的毒性作用最小。方法体外培养人外周血单个核细胞(peripheral blood mononuclear cells,PBMCs)并用抗CD3抗体激活,测定PBMCs增殖达到最活跃状态的时间;在PBMCs增殖最活跃时添加梯度浓度的卡铂,绘制PBMCs存活率-卡铂浓度曲线,计算使PBMCs存活率不低于90%的卡铂“安全浓度”,并根据文献中卡铂的体内药-时曲线推测卡铂“安全浓度”所对应的时间;在免疫抑制条件下添加抗PD-1抗体,测定抗PD-1抗体使PBMCs增殖达到最活跃状态所需的时间,计算PD-1单抗与卡铂联用的时序。结果PBMCs由抗CD3抗体激活后增殖加速(P<0.05),在第4天达到最大增殖率。卡铂浓度不超过3.981µmol/L时,对PBMCs的体外毒性作用较小。PD-L1蛋白可抑制PBMCs增殖(P<0.01),在PD-L1蛋白存在时,抗PD-1抗体使PBMCs达到最大增殖率需要96 h。结论先使用卡铂、后使用PD-1免疫检查点抑制剂的给药顺序对自身淋巴细胞的毒性更低;若先使用PD-1单抗、后使用卡铂,则二者给药间隔最好不要超过86 h,否则卡铂对淋巴细胞的毒性较大。
Background Currently,chemotherapy combined with immunotherapy is being widely used in treating various types of tumors,but the optimal combination timing of the two is inconclusive.Objective To optimize the sequence and interval between carboplatin and PD-1 immune checkpoint inhibitors(ICIs),so as to minimize the toxic effect of this combination regimen on immune cells.Methods Human peripheral blood mononuclear cells(PBMCs)were cultured in vitro and activated by anti-CD3 antibody,and the time when the proliferation of PBMCs reached the most active state was determined.Carboplatin was added at this time point,and the PBMCs survival rate-carboplatin concentration curve was plotted.The"safe concentration"of carboplatin that makes the survival rate of PBMCs not less than 90% was calculated,and the time corresponding to the"safe concentration"of carboplatin according to the in vivo drug time curve of carboplatin in the literature was speculated.Under the condition of immunosuppression,the time required for PD-1 antibody to bring the PBMCs’proliferation of to the most active state was determined,and the optimal sequence and interval of PD-1 ICIs in combination with carboplatin was calculated.Results PBMCs reached maximum proliferation rate on day4 after activation by CD3 antibody.Carboplatin concentrations less than 3.981μmol/L had a low toxic effect on PBMCs in vitro.In the presence of PD-L1 protein,it took 96 h for the anti-PD-1 antibody to bring PBMCs to a maximal proliferation rate.Conclusion The order of administration of carboplatin first,followed by PD-1 immune checkpoint inhibitors is less toxic to autologous lymphocytes.If PD-1 monoclonal antibody is used first,followed by carboplatin,the interval between the two administrations shouldn't exceed 86 h,otherwise,carboplatin will be more toxic to lymphocytes.
作者
孙小惠
邵佳康
李珂
龚一心
张孟
邱鲁鹏
孙卓雅
焦顺昌
SUN Xiaohui;SHAO Jiakang;LI Ke;GONG Yixin;ZHANG Meng;QIU Lupeng;SUN Zhuoya;JIAO Shunchang(Chinese PLA Medical School,Beijing 100853,China;Department of Oncology,the First Medical Center,Chinese PLA General Hospital,Beijing 100853,China;Department of Research and Development,Beijing DCTY®Biotech Co.,Ltd,Beijing 102200,China)
出处
《解放军医学院学报》
CAS
2024年第8期847-853,共7页
Academic Journal of Chinese PLA Medical School
基金
国家自然科学基金面上项目(81972681)。
关键词
免疫检查点抑制剂
人外周血单个核细胞
卡铂
药物联合治疗
治疗时间窗
immune checkpoint inhibitors
peripheral blood mononuclear cells
carboplatin
combination drugtherapy
door to treatment time
