A prospective randomized comparison of single-agent interferon (IFN)-alpha with the combination of IFN-alpha and low-dose IFN-gamma in chronic myelogenous leukaemia.

In patients with previously untreated chronic myelogenous leukaemia (CML) the efficacy of single-agent interferon (IFN)-alpha at an initial dose of 4 x 10(6) U/m2 (arm A) was compared with the combined administration of the identical dose IFN-alpha plus a total dose of 50 micrograms IFN-gamma (arm B). 51 patients entered this study between April 1987 and October 1989; the analysis was performed in March 1991 and was focused on response rates and toxicity. 54% of patients on arm A and 56% of arm B patients attained haematologic remission. 29% of patients on arm A and 24% of arm B patients had partial haematologic remission. A decrease in Philadelphia chromosome (Ph)-positive metaphases of more than 10% was only seen in patients who had achieved complete haematologic normalization. In 21% of patients on arm A and 20% of arm B patients, the percentage of Ph-positive cells declined to less than 35%. Toxicity was different between the two study groups with more pronounced hepatotoxicity observed in patients treated with IFN-alpha alone. Among the patients receiving both IFNs, alpha and gamma, there were 2 fatal infectious complications. This serious toxicity in conjunction with lack of a clinically meaningful difference between the two treatment schedules has led us to terminate the study. In conclusion, the addition of low-dose IFN-gamma failed to improve the efficacy of IFN-alpha in this study.     

Natural Interferon-Alpha Alone and in Combination with Conventional Therapies in Non-Small Cell Lung Cancer

Fourteen previously untreated patients with non-small cell lung cancer (NSCLC) were treated with natural interferon-alpha (IFN) in combination with conventional therapies. The planned dose of IFN was 6 × 10⁶ IU/d.i.m. 5 days a week for 12 weeks. After 12 weeks of IFN monotherapy patients with M0 disease underwent twice-daily fractionated radiotherapy (RT), 55 Gy/4F/30d, while IFN continued. Patients with M1 disease received 3 cycles of chemotherapy (CT) concomittantly with IFN. CT consisted of cisplatinum (P) 90 mg/m² i.v. on days 1, 28, and 56 and of vindesine (VDS) 3 mg/m² i.v. once a week 5 times and every other week thereafter for up to 8 courses. Thirteen patients were evaluable for response and toxicity. There were 9 patients with epidermoid, 3 with adeno- and one with large cell carcinoma. In 12 of 13 patients, the disease remained stable for 1 month during IFN monotherapy and one acheived a minimal response, which lasted 4 weeks. Of seven patients who completed the 12-week course of IFN monotherapy, 4 achieved stable disease (SD) and 3 had progressive disease. Three patients received RT and one received CT in combination with IFN as their subsequent treatment. There were 3 partial responses (2/3 after RT + IFN, 1/1 after CT + IFN), and 1 SD. Fatigue and weight loss were the most severe side-effects during IFN monotherapy. The combination of IFNs with conventional therapies might be clinically useful. We recommend further testing in larger studies.     

噬菌体呈现技术研制特异性人抗骨肉瘤干扰素

目的利用噬菌体表面呈现技术研制高活性、特异性抗骨肉瘤干扰素。方法将干扰素IFNαlc／86DDNA插入噬菌体质粒载体pCANTAB5E,并构建噬菌体IFNαlc／86DAB环突变文库;通过在OS732细胞上竞争性亲合洗脱、MTT法对比检测抗肿瘤活性,筛选针对OS732细胞的高活性噬菌体-IFN突变体。结果获得2个噬菌体-IFN突变体,其抗OS732细胞增殖活性较突变母体分别提高4和16倍。结论αl型干扰素可在噬菌体表面正确折叠表达。这一技术可用于研制高活性特异性IFN。     

聚乙二醇α干扰素治疗54例小儿慢性丙型肝炎报道

目的　对5 4例小儿慢性丙型肝炎(CHC)采用聚乙二醇α2a干扰素进行抗病毒治疗前瞻性研究。方法　以α干扰素1～3MIU诱导治疗后,聚乙二醇α2a干扰素剂量为每周10 4 μg m2 体表面积。利巴韦林剂量为15～2 0mg·kg 1 ·d 1 。结果　本组4 2 6 %CHC患儿经标准α干扰素联合利巴韦林治疗失败,70 8%患儿为HCVRNA基因Ⅰ型;14 8%患儿为高病毒载量。联合治疗3个月后87 5 %患儿HCVRNA阴转,8 3%HCVRNA下降≥2log。治疗6个月后87 9%HCVRNA阴转,6 1%HCVRNA下降≥2log。发生轻度流感样症状患儿为5 1 9% ,发热4 8 1% ,且多为低热。乏力4 6 3% ,食欲下降9 3% ,皮疹3 7%。患儿血中性粒细胞计数≤2 0×10 9 L为94 4 % ,其中<1 0×10 9 L为35 2 %。仅2例患儿血红蛋白降低。结论　采用聚乙二醇α2a干扰素联合利巴韦林治疗小儿CHC取得较高的病毒学应答,没有发生严重的不良反应。     

New aspects of immunotherapy of leptomeningeal metastasis

Immunotherapeutic approaches to leptomeningeal metastasis (LM) include the intrathecal application of cytokines such as interleukin-2 (IL-2) and interferon- (IFN-), and lymphokine-activated killer cells (LAK cells). Results in a rodent model of leptomeningeal gliomatosis with intrathecal IL-2 application are discouraging, but some clinical improvement and clearance of neoplastic cells from CSF have been seen in patients with LM from melanoma treated with intrathecal IL-2 alone, and in patients with LM from primary brain tumors and squamous cell carcinoma of the tongue treated with intrathecal LAK cells and IL-2. The neurotoxicity of this therapy, mainly increased intracranial pressure, has been considerable but generally manageable. However, IFN- caused severe neurotoxicity in form of an only partly reversible progressive vegetative state in the majority of patients. Considering the small number of patients treated with IL-2 and LAK cells, its value for the treatment of LM could only be stated by further investigation. In future, the application of recently discovered cytokines such as Fas-ligand, the continuous paracrine cytokine release by genetically modified cells, or vaccination strategies using genetically modified tumor cells might offer new immunotherapeutic approaches in LM.     

肌肉电脉冲转移入α2干扰素基因的表达和抗肿瘤作用(英文)

目的:研究肌肉电脉冲转移人α2干扰素基因的表达和抗肿瘤作用。方法:先将pcD_2/hIFN-α2注射到雌性BALB/c小鼠或荷瘤雌性BALB/c裸鼠的股四头肌内,然后在注射部位给予电脉冲刺激,以hIFN-α2 ELISA试剂盒研究最佳的电脉冲转移参数和转移效率;应用裸鼠移植HL-60瘤模型研究肌肉电脉冲转移人α干扰素基因的抗肿瘤作用。结果:当电脉冲参数为:电压200 V/cm,波宽40ms,脉冲次数6次和频率1Hz时,可获得最高的基因表达,此时,电脉冲组的IFN-α2水平(160μg/L±31μg/L)是直接注射组IFN- α2(3.6 μg/L±1.6 μg/L)水平的45倍(P<0.01),肌肉电脉冲转移100μg或200μg pcD_2/hIFN-α2明显抑制HL-60荷瘤裸鼠肿瘤细胞的生长和延长荷瘤裸鼠的生存时间。结论:肌肉电脉冲介导的基因转移是一种有效的基因转移方法,采用此方法转移pcD_2/hIFN-α2可有效治疗白血病。     

Citalopram for the Prevention of Depression and Its Consequences in HIV-Hepatitis C Coinfected Individuals Initiating Pegylated Interferon/Ribavirin Therapy: A Multicenter Randomized Double-Blind Placebo-Controlled Trial

Background: Depression related to interferon-alpha (IFN-α) is common, may reduce adherence, and can be treatment limiting. HIV-HCV coinfected persons experience lower sustained virologic response rates and commonly have psychiatric comorbidities, thus they may benefit from prevention of depression. Objective: The aim of the study was to determine whether prophylactic citalopram can increase HCV treatment adherence and reduce the incidence of moderate depression in HIV-HCV coinfected patients initiating PEG-IFN-α/ribavirin therapy. Methods: This was an investigator-initiated Canadian multicenter randomized, double-blind placebo-controlled trial. HIV-HCV coinfected patients were randomized in a 1:1 ratio to receive citalopram or placebo 3 weeks prior to starting PEG-IFN-α2b/ribavirin, stratified by study center and HCV genotype. The protocol design permitted the comparison of prophylaxis with the treatment of emergent depression. The primary outcomes were adherence (assessed through questionnaire and returned medication) and time to moderate depression measured by Beck Depression Inventory-II (BDI-II) score greater than 15, confirmed 2 weeks apart. Results: Seventy-six patients (36 citalopram/40 placebo) were randomized. Overall adherence was high, ranging from 95% (week 12) to 91% (week 48). There was no difference between arms with respect to mean or median adherence at any study time point. Cumulative incidence of moderate depression did not differ significantly by group (log rank P = .32). The hazard ratio for moderate depression was 0.81 (95% CI, 0.26 to 2.54) for citalopram compared with placebo when adjusted for baseline BDI-II score. Conclusions: A strategy of prophylactic citalopram compared to treatment of emergent depression was not associated with higher adherence or a reduction in treatment-limiting depression nor did it significantly reduce depressive symptoms among HIV-HCV coinfected persons during treatment for HCV.     

Lack of evidence for the Th2 predominance in patients with chronic hepatitis C

A T helper (Th)1 to Th2 shift has been proposed to be a critical pathogenic determinant in chronic hepatitis C. Here, we evaluated mitogen-induced and hepatitis C virus (HCV) core antigen-induced cytokine production in 28 patients with biopsy-proven chronic hepatitis C. Flow cytometry demonstrated that after mitogenic stimulation the percentage of Th2 cells (IL-4 + or IL-13 +) and Th0 cells (IFN-gamma/IL-4 + or IL-2/IL-13 +) did not differ between patients and controls. In contrast, the percentage of Th1 cells (IFN-gamma + or IL-2 +) was significantly increased in CD4 +, CD8 +, 'naive'-CD45RA + and 'memory'-CD45RO + T-cell subsets from patients versus controls. Similar results were obtained by ELISA testing supernatants from mitogen-stimulated, unfractionated peripheral blood mononuclear cell (PBMC) cultures. Interferon-alpha treatment was associated with a reduction in the mitogen-induced Th1 cytokine response in those patients who cleared their plasma HCV-RNA. Analysis of cytokine expression by CD4 + T cells after HCV core antigen stimulation in a subgroup of 13 chronic hepatitis C patients demonstrated no cytokine response in 74% of these patients and an IFN-gamma-restricted response in 26%. Finally, no Th2 shift was found in lipopolysaccharide-stimulated monocytes. These data indicate that a Th1 to Th2 shift does not occur in chronic hepatitis C.     

Interferon-Alpha Therapy in Liver Transplant Recipients: Lack of Association with Increased Production of Anti-HLA Antibodies

Interferon-alpha (IFN) is a useful treatment for active HCV infection. In kidney transplantation, IFN has been shown to trigger acute rejection with de novo anti-HLA antibodies. Interferon-alpha has not been reported to enhance the risk of acute rejection in HCV-positive liver transplant recipients (LTRs). Sera were collected from 44 LTRs greater than 6 months post-transplant. Sera were tested with ELISA for the presence and the specificity of anti-HLA antibodies. The prevalence of anti-HLA antibodies was 11% and was not significantly different in 13 HCV-positive recipients who received IFN, compared with 10 who did not receive IFN (8% vs. 20%), or with 21 HCV-negative recipients (10%). None of the patients had an acute rejection after starting IFN. In this study, LTRs receiving IFN did not have an increased frequency of anti-HLA antibodies. This may partially explain the safety of IFN previously reported in LTRs requiring antiviral therapy.