[Effects of auto-tumor infiltrating lymphocytes induced by interleukin (IL)-12 with IL-2 on patients of primary hepatic carcinoma].
OBJECTIVE
To investigate the effects of the tumor infiltrating lymphocytes (TILs) from primary hepatic carcinoma (PHC) induced by interleukin-12 (IL-12) with IL-2, on their cytotoxicity, proliferation, and cytokine production, and the immunological function and survival of the PHC patients.


METHODS
PHC cells and TILs were isolated from the resected tumors and cultured. IL-2 was added into the culture medium with or without IL-12. Ten to 14 days later the cytotoxic activity and proliferation index (PI) of the TILs were calculated. The levels of the cytokine interferon (IFR)-gamma and tumor necrosis factor (TNF)-alpha in the supernatant were tested by ELISA. 20-25 days after the operation the TILs were re-infused into the bodies. The clinical manifestation, cytotoxicity of TILs, phenotype of peripheral blood lymphocytes, and survival of patients were observed.


RESULTS
1. The cytotoxicity of the TILs of the IL-12 + IL-2 group against the autologous hepatic carcinoma cells was greater than that of the TILs of the IL-2 group (P < 0.05). 2. The PI of the TILs of the IL-12 + IL-2 group was 17.78%, significantly higher than that of the IL-2 group (10.9%, P < 0. 05). 3. The levels of IFN-gamma and TNF-alpha of the IL-12 + IL-2 group were (2180 +/- 494) pg/ml and(485 +/- 98) pg/ml, both significantly higher than those of the IL-2 group [(1078 +/- 309.46) pg/ml and (422.00 +/- 15.81) pg/ml, both P < 0. 05]. 4. After re-infusion of TILs, the CD3+, CD8+, CD4+, and CD56+ rates, especially the CD3+ and CD8+ rates, of the IL-12 + IL-2 group were all significantly higher than those of the IL-2 group (all P < 0.05). 5. After TIL re-infusion the clinical manifestation of all patients were improved. 6. 23 of the 25 patients receiving the re-infusion of the TILs of the IL-12 + IL-2 group survived for more than 1 year, with a rate significantly higher than that of the IL-2 group (17/25, chi2 = 4.5, P < 0.05), however, there were no significant differences in the 3-year and 5-year survival rates between these 2 groups (both P > 0.05). The number of patients who showed recurrence in less than 1 year was 17 in the IL-2 group, with a rate significantly higher that of the IL-12 + IL-2 group (8/25, chi2 = 4.32, P < 0.0 5). However, there was no significant difference in the recurrence rate < or = 3 years between these 2 groups (chi2 = 1.56, P > 0.05).


CONCLUSIONS
TILs from primary hepatic carcinoma induced by IL-12 can obviously enhance specific cytotoxicity and proliferation of TILs. TILs induced by IL-12 + IL-2 increase the patients' immunological function, prolong the 1-year survival, and decreases recurrence more effectively than the TILs induced by IL-2 only.
Zhang
Yi-Xin
YX
Nangtong Tumor Hospital of Nantong University, Nantong 226361, China.
Wang
Xiao-Ying
XY
Liu
Ji-Bin
JB
Zhang
Su-Qing
SQ
Chen
Yi-Ren
YR