Adoptive transfer of tumor-reactive transforming growth factor-beta-1 insensitive cytolytic T cells for treatment of established mouse Renca tumors

Abstract

OBJECTIVES To test, using a mouse renal cancer, Renca, whether adoptive transfer of tumor-reactive transforming growth factor (TOF)-beta-insensitive cytolytic T cells can inhibit tumor progression. METHODS Cytolytic T cells were isolated from the spleen of male Balb/c mice repeatedly primed with irradiated Renca cells. They were expanded ex vivo and were rendered TGF-beta-insensitive by infecting with a retrovirus containing dominant negative TGF-beta type II receptor. RESULTS These tumor reactive TGF-beta-insensitive cytolytic T cells showed a specific and robust tumor killing activity against Renca cells, but not irrelevant cells, using an in vitro cytotoxic assay. Adoptive transfer of cytolytic T cells was performed in mice 10 days after they were challenged with Renca cells (5 X 10(5)) by tail vein injection. At 30 days after the adoptive transfer, the pulmonary tumor Counts in mice who had received TGF-beta-insensitive cytolytic T cells (mean +/- standard deviation 130 140) was significantly less than those in mice that had received TGF-beta-sensitive cytolytic T cells (305 +/- 60) or in mice had received naive cytolytic T cells (375 +/- 50; P <.01). Kaplan-Meier survival analysis indicated that mice that had received adoptive transfer of TGF-beta-insensitive cytolytic T cells had a significantly greater rate of survival (75%) compared with mice that had received TGF-beta-sensitive cytolytic T cells (35%) or naive cytolytic T cells (15%), respectively (P <.05). CONCLUSIONS These results suggest that adoptive transfer of tumor- re active TGF-beta-insensitive cytolytic T cells can warrant consideration for renal cell cancer immunotherapy.