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 T-cells in vitro and activate specific and nonspecific cytolysis by human T-cell clones and human peripheral blood lymphocytes. In vivo administration of anti-CD3 prevents tumor growth of a UV-induced mouse fibrosarcoma. 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 mcg/patient. Five other patients received anti-CD3 at 30 mcg 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 mcg 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 meningeal 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 mcg. 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 CD25 (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-CD3, 8 of 16 patients tested developed human anti-mouse antibodies.
Urba
W J
WJ
Clinical Services Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702-1201.
Ewel
C
C
Kopp
W
W
Smith
J W
JW
Steis
R G
RG
Ashwell
J D
JD
Creekmore
S P
SP
Rossio
J
J
Sznol
M
M
Sharfman
W
W
D000328:Adult; D000368:Aged; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006261:Headache / Q000209:etiology*; D006801:Humans; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000378:metabolism / Q000627:therapeutic use*; D009369:Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013129:Spinal Puncture
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016207:Cytokines; D016853:Muromonab-CD3; D011948:Receptors, Antigen, T-Cell