Sosman J A, Weiss G R, Margolin K A, Aronson F R, Sznol M, Atkins M B, O'Boyle K, Fisher R I, Boldt D H, Doroshow J
Loyola University Medical Center, Maywood, IL 60153.
J Clin Oncol. 1993 Aug;11(8):1496-505. doi: 10.1200/JCO.1993.11.8.1496.
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.
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.
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).
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.
确定抗CD3抗体OKT3与高剂量白细胞介素-2（IL-2）联合使用时的最大耐受剂量（MTD），并确定OKT3是否能增强晚期黑色素瘤和肾细胞癌患者接受高剂量IL-2治疗时外周血中表达CD3⁺、CD25⁺（白细胞介素-2受体α[IL-2Rα]）的T细胞的扩增。
我们对晚期黑色素瘤和肾细胞癌患者进行了一项鼠单克隆抗CD3抗体（OKT3）与高剂量IL-2联合使用的ⅠB期试验。共纳入54例患者，每组10例或更多患者，在第1天接受递增剂量的OKT3，剂量分别为75、200、400和600μg/m²，随后在第2至6天和第16至20天接受IL-2，初始剂量为0.45mg/m²，然后每8小时1.33mg/m²（最大剂量，28剂）。另外一组14例患者单独接受高剂量IL-2（每剂1.33mg/m²）。在治疗前和IL-2治疗的第一周后监测循环中的CD3⁺、CD25⁺细胞。
共纳入68例患者。基于可给予的IL-2剂量减少，OKT3的MTD定义为400μg/m²。在所有组中均观察到CD3⁺、CD25⁺细胞增加；然而，这种增加并非与OKT3剂量相关。另一方面，我们发现，在接受200、400和600μg/m² OKT3剂量水平检测的患者中，60%（15例中的9例）血清可溶性CD25（可溶性IL-2Rα）增加至超过100,000U/mL，而在接受75μg剂量的单独IL-2或与OKT3联合治疗的10例患者中，无一例增加超过60,000U/mL。在29例接受OKT3与IL-2（1.33mg/m²）联合治疗的肾细胞癌患者中，有3例出现客观肿瘤反应（均为部分反应）。在16例接受OKT3加IL-2治疗的黑色素瘤患者中，有1例出现客观反应（完全反应）。
按此方案给予的OKT3剂量未能显著增加循环中CD3⁺、CD25⁺ T细胞数量，且单独使用时似乎并未增加IL-2的抗肿瘤活性，这突出了需要采用其他方法来提高IL-2治疗的疗效。
