Functional and phenotypic analysis of tumor-infiltrating. Lymphocytes isolated from human primary and metastatic. Liver tumors and cultured in recombinant interleukin-2

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Abstract
Tumor-infiltrating lymphocytes (TIL) were isolated from 40 of 51 consecutive human liver tumor samples (primary hepatocellular carcinoma, 16 of 18; metastatic, 23 of 29; benign, one of four). Functional and phenotypic characteristics of fresh and recombinant interleukin-2 (rlL-2)-expanded TIL were evaluated. The expansion of TIL from metastatic liver tumors in the presence of 1000 units/ml of rIL-2 was possible in 60% of cases. In comparison to TIL from metastatic liver tumors, TIL obtained from primary liver tumors expanded faster and better in rIL-2 cultures. Expanded TIL from primary tumors had significantly higher cytotoxicity against K562 targets, but not Raji targets, than those from metastatic tumors. Cytotoxicity against fresh autologous tumor targets was detected in seven of eight cultures tested. TIL from primary tumors retained antitumor reactivity significantly longer in culture. The optimal in vitro cytotoxicity was achieved between days 20 and 60 of culture in the presence of rIL-2. Antitumor activity was associated with the increase in these TIL cultures of a cell population expressing the Leul9 antigen with or without the CD3 antigen. The frequency of the CD3+Leul9+ population showed a bimodal distribution during culture: the first peak of CD3+Leul9+ cells occurred between days 30 and 60 and was associated with the increased antitumor activity; the second peak occurred after day 60 and was not associated with activity. These findings demonstrate that TIL from most human hepatic tumors can be successfully isolated, cultured in rIL-2, and enriched in Leul9+ effectors. In addition, these TIL upon IL-2 activation in vitro are capable of lysing fresh autologous and/or allogeneic tumor targets.

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