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

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.