Clinical and immunological effects of treatment with murine anti-CD3 monoclonal antibody along with interleukin 2 in patients with cancer

Anti-CD3 mAb and interleukin 2 (IL-2) were used in a Phase I study to treat 29 patients with cancer, The anti-CD3 was given as an i,v. bolus infusion over 10 min followed by two i,v, 96-h continuous infusions of IL-2 at 3 x 10(6) units/ m(2)/day with a 3-day rest between the IL-2 infusions. Pour patients were treated with 6, 18, 60, and 300 mu g/m(2) anti-CD3, One patient received 3000 mu g/m(2) anti-CD3, This patient developed profound hypotension and the IL-2 infusions were delayed for 2 weeks. Two patients were treated at an intermediate dose of 600 mu g/m(2). These patients developed dose-limiting toxicities including hypotension, dyspnea and increased blood urea nitrogen, creatinine, and bilirubin, They were unable to complete their first course of therapy. In an effort to achieve a dose of anti-CD3 which would activate T cells in vivo, pentoxifylline was given to blunt the toxicities seen with anti-CD3 thought to be due predominantly to the cytokine syndrome and tumor necrosis factor release. Four patients received p,o, pentoxifylline to cover an anti-CD3 dose of 600 mu g/m(2), The IL-2 infusion was initiated 1 week after the mAb, While there was an anti-CD3 dose-dependent increase in serum tumor necrosis factor level 1 h after mAb infusion, pentoxifylline did not reduce the serum tumor necrosis factor level, There was also an anti-CD3 dose-dependent increase in the serum soluble IL-2 receptor levels, Other immune parameters monitored, including in vitro cytotoxic and proliferative responses and lymphocyte count, mere similar to treatment courses with IL-2 alone, Fourteen of 26 patients examined developed human anti-murine antibodies following a single dose of anti-CD3, There were no objective antitumor responses, We conclude that in vivo treatment with anti-CD3 did not enhance T cell activity or expansion with subsequent IL-2 infusion and that the combination of anti-CD3 followed by IL-2 did not improve upon the antitumor activity previously seen with IL-2 alone.