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/m2/day with a 3-day rest between the IL-2 infusions. Four patients were treated with 6, 18, 60, and 300 microgram/m2 anti-CD3. One patient received 3000 microgram/m2 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 microgram/m2. 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 microgram/m2. 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, were 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.
Hank
J A
JA
Departments of Human Oncology, Pediatrics, and Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.
Albertini
M
M
Wesly
O H
OH
Schiller
J H
JH
Borchert
A
A
Moore
K
K
Bechhofer
R
R
Storer
B
B
Gan
J
J
Gambacorti
C
C
D000920:Antibody-Dependent Cell Cytotoxicity; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004417:Dyspnea; D006801:Humans; D007022:Hypotension; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008213:Lymphocyte Activation; D016853:Muromonab-CD3 / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D009369:Neoplasms / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D015375:Receptors, Interleukin-2 / Q000097:blood; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015415:Biomarkers; D007376:Interleukin-2; D016853:Muromonab-CD3; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha