title: Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) of an anti-CD3 antibody, OKT3, in combination with high-dose interleukin-2 (IL-2), and to determine whether OKT3 can enhance the expansion of CD3+, CD25+ (IL-2 receptor alpha [IL-2R alpha])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2.
  
  
  METHODS
  We performed a phase IB trial of a murine monoclonal anti-CD3 antibody (OKT3) with high-dose IL-2 in patients with advanced melanoma and renal cell carcinoma. Fifty-four patients were enrolled, with cohorts of 10 or more patients receiving escalating doses of OKT3 at 75, 200, 400, and 600 micrograms/m2 on day 1 followed by IL-2 at an initial dose 0.45 and then 1.33 mg/m2 every 8 hours on days 2 through 6 and 16 through 20 (maximum, 28 doses). An additional cohort of 14 patients received high-dose IL-2 (1.33 mg/m2 per dose) alone. Circulating CD3+, CD25+ cells were monitored before therapy and following the initial week of IL-2.
  
  
  RESULTS
  A total of 68 patients were enrolled. The MTD for OKT3 was defined as 400 micrograms/m2 based on a reduction in the number of IL-2 doses that could be administered. Increases in CD3+, CD25+ cells were observed within all cohorts; however, the increase was not OKT3 dose-dependent. On the other hand, we found that 60% (nine of 15) of patients tested at OKT3 dose levels of 200, 400, and 600 micrograms/m2 had increases in serum sCD25 (soluble IL-2R alpha) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-micrograms dose had increases greater than 60,000 U/mL. Of 29 patients with renal cell carcinoma who received OKT3 with IL-2 (1.33 mg/m2), there were three objective tumor responses (all partial responses). In the 16 patients with melanoma who received OKT3 plus IL-2, there was a single objective response (complete response).
  
  
  CONCLUSIONS
  The doses of OKT3 administered on this schedule failed to enhance significantly the number of circulating CD3+, CD25+ T cells and did not appear to increase the antitumor activity of IL-2 alone, which underscores the need for other approaches to enhance the efficacy of IL-2 therapy.
authors.affiliation: Loyola University Medical Center, Maywood, IL 60153.
authors.forename: J A
authors.initials: JA
authors.lastname: Sosman
authors.forename: G R
authors.initials: GR
authors.lastname: Weiss
authors.forename: K A
authors.initials: KA
authors.lastname: Margolin
authors.forename: F R
authors.initials: FR
authors.lastname: Aronson
authors.forename: M
authors.initials: M
authors.lastname: Sznol
authors.forename: M B
authors.initials: MB
authors.lastname: Atkins
authors.forename: K
authors.initials: K
authors.lastname: O'Boyle
authors.forename: R I
authors.initials: RI
authors.lastname: Fisher
authors.forename: D H
authors.initials: DH
authors.lastname: Boldt
authors.forename: J
authors.initials: J
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000627:therapeutic use*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes
chemical_list: D007376:Interleukin-2; D016853:Muromonab-CD3; D015375:Receptors, Interleukin-2