白细胞介素12诱导肝癌肿瘤浸润淋巴细胞的临床应用

Clinical study on the tumor infiltrating lymphocytes of liver cancer induced by interleukin 12

目的 :对 IL -12 + IL -2培养的肝癌肿瘤浸润淋巴细胞 (TIL)与 IL-2诱导的 TIL作对照研究观察 TIL的特异性杀伤力、增殖能力、细胞因子的改变及临床疗效。方法 :将手术切除的原发性肝癌进行体外分离 ,分别用含 IL -2的培养液和含 IL-12 +IL-2的培养液培养 ,诱导 TIL的生长。培养 10～ 14天测定细胞杀伤率、细胞因子和增殖能力 ,待细胞扩增达 10 8～ 9· ml- 1 时进行回输 ,随访观察临床疗效。结果 :(1) IL-12 + IL -2组 TIL对自体肝癌细胞的细胞杀伤率比 IL -2组明显增高 (P<0 .0 1) ;(2 ) IL -12+ IL -2组 TIL比 IL-2组扩增能力明显增强 (P<0 .0 5 )。 (3 ) IL-12 + IL -2组较 IL-2组细胞因子γ干扰素 (IFN-γ)和肿瘤坏死因子 α(TNF-α)水平明显增高 (P<0 .0 5 )。 (4 ) TIL 回输后 IL-12 + IL-2组与 IL-2组 CD3+、CD4 +、CD8+均升高 ,以 CD3+、CD8+ 升高为主。与输注前比较差异均有显著性。 IL-12 + IL-2组与 IL-2组间比较 ,前者 CD3+ 、CD8+ 、CD56 + 上明显高于后者 ,差异显著 (P<0 .0 5 )。 (5 )患者的临床症状改善明显。 (6) IL-12 + IL-2组 1年、3年、5年生存率与 IL-2组 TIL回输肝癌患者对比差异均显著且复发率降低。结论 :白介素 12诱导肝癌 TIL可明显增强

Objective:To compare the effect on the cytotoxicity,proliferation, cytokine production of the tumor infiltrating lymphocytes (TIL) of liver cancer induced by interleukin-12 (IL-12) with interleukin-2 . To compare the subsets of lymphocytes, clinical manifestations and survival data of preoperative patients with infused patients. Methods:TILs derived from resected tumors in patients of primary hepatic cancer, which were cultured in complete culture medium in which IL-12 was added in with or without IL-2. The cytotoxic activity, augmentation ability and cytokine production were tested separately 10th to 14th days after the culture. TILs infusions have begun when the augmentation of TILs were about 10 8~9·ml -1.Results:(1)The cytotoxic activities of TILs to the autologous hepatic cancer cells induced by IL-12 with IL-2 were more strengthened than induced only by IL-2 (P<0.01).(2)The augmentation activities of TILs in IL-12+IL-2 group were higher than that in IL-2 group (P<0.05). (3)The secretions of IFN-γand TNF-αfrom TILs induced by IL-12+ IL-2 were higher than the TILs induced by IL-2(P<0.05).(4)After infusion of TILs,the CD 3+,and CD 8+ rates in IL-12+IL-2 group were significantly higher than that of IL-2 group(P<0.01), CD 4+ and CD 56+ rate were also significantly higher than that(P<0.05).(5)Better clinical manifestations were made.(6)The results of follow-up suggested that the survival rate of 1 year, 3year and 5 year were significantly higher in IL-12+IL-2 group than in IL-2 group and so were the recurrence rate.Conclusions:TILs of hepatic cancer induced by IL-12 can obviously enhance specific cytotoxicity and proliferation of TILs. To compare the IL-12+IL-2 group with the IL-2 group,the clinical results after infused TILs back into patients revealed that there were a great increase in patient`s immunological function, prolonged survival period and decreased recurrence rate.