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

J. A. Sosman*, G. R. Weiss, K. A. Margolin, F. R. Aronson, M. Sznol, M. B. Atkins, K. O'Boyle, R. I. Fisher, D. H. Boldt, J. Doroshow, M. L. Ernest, S. G. Fisher, J. Mier, G. Vachino, G. Caliendo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Purpose: 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 CD34, CD254 (IL-2 receptor α[IL-2Rα])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2. Patients and 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 μg/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 μg/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 1 5) of patients tested at OKT3 dose levels of 200, 400, and 600 μg/m2 had increases in serum sCD25 (soluble IL-2Rα) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-μg 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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1496-1505
Number of pages10
JournalJournal of Clinical Oncology
Volume11
Issue number8
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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