Bukowski R M, Olencki T, Wang Q, Peereboom D, Budd G T, Elson P, Sandstrom K, Tuason L, Rayman P, Tubbs R, McLain D, Klein E, Novick A, Finke J
Cancer Center Experimental Therapeutics Program, Cleveland Clinic Foundation, Ohio 44195, USA.
J Immunother. 1997 Jul;20(4):301-11. doi: 10.1097/00002371-199707000-00007.
A phase II trial was conducted in patients with metastatic renal cell carcinoma, to assess the clinical efficacy and immunoregulatory effects of continuous-infusion recombinant interleukin-2 (rIL-2) (9.0 x 10(6) IU/m2/day on days 1-5, 8-12, 15-19, and 22-26) and subcutaneously administered recombinant human interferon-alpha 2b (rHuIFN alpha 2b) (10.0 x 10(6) U/m2/day TIW). Thirty-six patients with metastatic renal cell carcinoma, performance status of 0-1, and measurable disease who had not received prior rIL-2, rHuIFN alpha 2b, or chemotherapy were treated. Patients with CNS metastases, active infections, history of another malignancy within 3 years, and those requiring corticosteroids were ineligible. Cycles of rIL-2 and rHuIFN alpha 2b were administered in the outpatient department every 6-8 weeks in stable or responding patients until patient tolerance or a complete response were reached. Doses were modified for grade III or IV toxicity. Ancillary studies included three-color immunocytometric analysis of peripheral blood lymphocytes, repetitive tumor biopsies for immunohistologic analysis of infiltrating cells and proliferative responses of tumor infiltrating lymphocytes, and preliminary studies of changes in peripheral blood T-lymphocyte signal transduction molecules [T-cell receptor (TCR)-zeta, p56ick, p59fyn]. Thirty-six eligible patients were treated, with 6 of 36 patients (17%, 95% confidence interval 6-33%) responding (3 complete response, 3 partial response). In two of the partial responders, and in an additional three patients with either minimal tumor regression (one patient) or stable disease (two patients), surgical removal of residual disease was undertaken. The median survival of all patients was 14 months. The toxicity of this regimen was severe, but outpatient administration was possible in most instances. Immunoregulatory effects on T-cell subsets included increases in various CD3+ CD25+/- HLADr+/- subsets unrelated to response. Tumor biopsies before and/or during therapy were obtained in 17 patients, and no consistent alterations in the degree of T-lymphocyte or macrophage infiltrates could be detected. In a subset of patients, tumor infiltrating lymphocyte proliferative responses and levels of peripheral blood T-cell signal transduction molecules (TCR-zeta, p56lck, p59fyn) were investigated. Abnormalities were found in selected patients, which improved during rIL-2/rHuIFN alpha 2b therapy. This cytokine combination produces tumor regression in selected patients with metastatic renal cell carcinoma. Surrogate immunologic markers associated with response were not identified; however, preliminary studies demonstrate investigation of immune defects and their reversal with cytokine therapy is possible.
对转移性肾细胞癌患者进行了一项II期试验，以评估持续输注重组白细胞介素-2（rIL-2）（第1 - 5天、8 - 12天、15 - 19天和22 - 26天，9.0×10⁶IU/m²/天）和皮下注射重组人干扰素-α2b（rHuIFNα2b）（10.0×10⁶U/m²/天，每周三次）的临床疗效和免疫调节作用。36例转移性肾细胞癌患者，体能状态为0 - 1，患有可测量疾病，且未接受过先前的rIL-2、rHuIFNα2b或化疗，接受了治疗。有中枢神经系统转移、活动性感染、3年内有其他恶性肿瘤病史以及需要使用皮质类固醇的患者不符合入组条件。对于病情稳定或有反应的患者，每6 - 8周在门诊给予rIL-2和rHuIFNα2b周期治疗，直至达到患者耐受或完全缓解。针对III级或IV级毒性调整剂量。辅助研究包括对外周血淋巴细胞进行三色免疫细胞分析、重复进行肿瘤活检以对浸润细胞进行免疫组织学分析以及肿瘤浸润淋巴细胞的增殖反应，以及对外周血T淋巴细胞信号转导分子 [T细胞受体（TCR）-ζ、p56ick、p59fyn] 变化的初步研究。36例符合条件的患者接受了治疗，36例患者中有6例（17%，95%置信区间6 - 33%）有反应（3例完全缓解，3例部分缓解）。在2例部分缓解者以及另外3例肿瘤有最小程度消退（1例患者）或病情稳定（2例患者）的患者中，进行了残余病灶的手术切除。所有患者的中位生存期为14个月。该方案的毒性严重，但在大多数情况下可以在门诊给药。对T细胞亚群的免疫调节作用包括各种与反应无关的CD3⁺CD25⁺/⁻HLADr⁺/⁻亚群增加。在17例患者中在治疗前和/或治疗期间获取了肿瘤活检样本，未检测到T淋巴细胞或巨噬细胞浸润程度的一致变化。在一部分患者中，研究了肿瘤浸润淋巴细胞增殖反应和外周血T细胞信号转导分子（TCR-ζ、p56lck、p59fyn）水平。在部分选定患者中发现了异常，这些异常在rIL-2/rHuIFNα2b治疗期间有所改善。这种细胞因子组合在选定的转移性肾细胞癌患者中产生肿瘤消退。未鉴定出与反应相关的替代免疫标志物；然而，初步研究表明对免疫缺陷及其通过细胞因子治疗的逆转进行研究是可行的。
