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Anti-CD3 Monoclonal Antibody Treatment of Patients with CD3-Negative Tumors: A Phase IA/B Study¹

Clinical Services Program, Program Resources, Inc./DynCorp [W. J. U., C. E., W. K., J. R., J. B.] and Biological Response Modifiers Program [J. W. S., R. G. S., J. D. A., S. P. C., W. S., R. F., J. J., D. L. L.], National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201; Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892 [M. S.]; and Frederick Memorial Hospital, Frederick, Maryland 21701 [T. W.]

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.

¹ This project has been funded at least in part with Federal funds from the Department of Health and Human Services under Contract N01-CO-74102. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

² To whom requests for reprints should be addressed, at Program Resources, Inc., National Cancer Institute-Frederick Cancer Research and Development Center, P. O. Box B, Frederick, MD 21702-1201.

Received 11/ 6/91. Accepted 2/20/92.

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