Yang S C, Grimm E A, Parkinson D R, Carinhas J, Fry K D, Mendiguren-Rodriguez A, Licciardello J, Owen-Schaub L B, Hong W K, Roth J A
Department of Thoracic Surgery, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Cancer Res. 1991 Jul 15;51(14):3669-76.
Sixteen patients with metastatic non-small cell lung cancer were treated with a combination of simultaneous low-dose interleukin 2 (IL-2) and tumor necrosis factor alpha. The purpose of this phase I dose escalation trial was to assess the clinical toxicities, immunomodulatory effects, and antitumor efficacy of this combination. Patients received a continuous daily i.v. infusion of 6 x 10(6) IU/m2 of IL-2 for 5 days and a concomitant daily i.m. dose of tumor necrosis factor alpha on each day of IL-2 administration. Tumor necrosis factor alpha administration started at a dose of 25 micrograms/m2/day (level I) for seven patients, 50 micrograms/m2/day (level II) for seven patients, and 100 micrograms/m2/day (level III) for two patients. Treatment was given at 3-week intervals. Only one patient required monitoring by an intensive care unit during therapy. Major toxic effects included fever, local skin reaction at the i.m. injection site, pancytopenia, and general malaise, all of which were reversible within 48 h of cessation of therapy. Dose level II was determined to be the maximum tolerated dose, with the dose-limiting toxicity being thrombocytopenia (less than 50,000/microliters). In 12 evaluable patients, one partial and three minor tumor regressions were observed. Seven patients with progressive disease before entry into this study had radiographic stabilization of their disease (median, 12 weeks) before termination of therapy due to progression. All patients exhibited biological responses including augmented lymphokine-activated killer and natural killer cell activities while receiving therapy, as assessed by the cytolysis of Raji- and K562 targets in vitro. Enhanced lysis of autologous tumor during therapy was demonstrated for four patients with available tumor samples. Serum levels of IL-2 were detected by enzyme-linked immunosorbent assay 2 weeks after cessation of therapy. This serum IL-2 had biological activity, which was evident from the ability to induce proliferation of NK-8 cells (an IL-2-dependent cell line) which was abrogated by anti-IL-2 antibody.
16例转移性非小细胞肺癌患者接受了低剂量白细胞介素2（IL-2）与肿瘤坏死因子α联合治疗。这项I期剂量递增试验的目的是评估该联合治疗的临床毒性、免疫调节作用和抗肿瘤疗效。患者连续5天每天静脉输注6×10⁶IU/m²的IL-2，并在给予IL-2的每一天同时皮下注射肿瘤坏死因子α。7例患者肿瘤坏死因子α的起始剂量为25μg/m²/天（I级），7例患者为50μg/m²/天（II级），2例患者为100μg/m²/天（III级）。治疗每3周进行一次。治疗期间只有1例患者需要重症监护病房进行监测。主要毒性反应包括发热、皮下注射部位局部皮肤反应、全血细胞减少和全身不适，所有这些在治疗停止后48小时内均可逆转。II级剂量被确定为最大耐受剂量，剂量限制性毒性为血小板减少（低于50,000/μl）。在12例可评估的患者中，观察到1例部分缓解和3例轻度肿瘤消退。7例在进入本研究前病情进展的患者在因病情进展终止治疗前，其疾病影像学表现稳定（中位数为12周）。所有患者在接受治疗时均表现出生物学反应，包括增强的淋巴因子激活的杀伤细胞和自然杀伤细胞活性，这通过体外Raji和K562靶细胞的细胞溶解来评估。4例有可用肿瘤样本的患者在治疗期间显示出对自体肿瘤的裂解增强。治疗停止2周后通过酶联免疫吸附测定法检测血清IL-2水平。这种血清IL-2具有生物学活性，这从其诱导NK-8细胞（一种IL-2依赖细胞系）增殖的能力中可以明显看出，而抗IL-2抗体可消除这种能力。
