Anti-CD3 monoclonal antibody treatment of patients with CD3-negative tumors: a phase IA/B study.

Anti-CD3 monoclonal antibodies induce the proliferation of human I - cells in vitro and activate specific and nonspecific cytolysis by human T- cell clones and human peripheral blood lymphocytes. In vivoadministra tion of anti-CD,! prevents tumor growth of a UV-induced mouse fibro sarcoma. We conducted a phase I trial to determine the toxicity and immunomodulatory properties of low doses of anti-CD3 in 36 patients with cancer. In 23 patients, anti-CD3 was given i.v. over 3 h at 1, 10, 30, and 100 meg/patient. Five other patients received anti-CD3 at 30 meg by i.v. bolus. Patients were treated every 3 days for a total of four doses. An additional eight patients received anti-CD3 daily for 14 days at 3 meg by i.v. bolus, 3-h infusion, or 24-h infusion. Dose-limiting toxicity was headache. Headache was often accompanied by signs and symptoms of meningea! irritation leading to performance of a lumbar puncture in nine patients. The opening pressure was usually elevated, and six patients had a cerebrospinal fluid lymphocytosis with an elevated protein. Increased levels of interleukin 6 were identified in the cerebrospinal fluid. The maximum tolerated dose by 3-h infusion was 30 meg. There were no objective tumor responses. There was a dose-related increase in the number of peripheral blood lymphocytes expressing the T-cell activation antigen CD69 (Leu 23), but no changes were seen in CD2S (interleukin 2 receptor) expression, and no changes were observed in the serum levels of the soluble interleukin 2 receptor. Even at these low doses of anti- CD,!, 8 of 16 patients tested developed human anti-mouse antibodies.