Regimens with or without interferon-alpha as treatment for metastatic melanoma and renal cell carcinoma: an overview of randomized trials

The effect of interferon-alpha (IFN-alpha) as single agent or in combination in the treatment of metastatic malignant melanoma (MM) or of advanced renal cell carcinoma (RCC) has been widely explored in phase II trials. To evaluate the net benefit of IFN-alpha therapy in these diseases, we performed a meta-analysis comprising all available randomized trials comparing regimens with or without IFN-alpha. Data were obtained from the Medline data base, and from the data bases at the National Cancer Institute, Schering-Plough, and Hoffmann-La Roche. A total of six published and five unpublished studies on metastatic MM, as well as six published and two unpublished studies on advanced RCC, comprising altogether 1,164 and 525 patients, respectively, fulfilled our criteria. In MM, the overall response rate for the IFN-alpha-containing regimens was 24% (range, 10-46%), compared with 17% (range, 5-30%) for those without IFN-alpha. In RCC, the overall response rate for IFN-alpha-containing regimens was 14% (range, 4-33%), and 8% (range, 3-27%) for those without IFN-alpha. A meta-analysis showed that regimens including IFN-alpha improved response rates compared with regimens without IFN-alpha. The pooled odds ratio (OR) for improved response with IFN-alpha in metastatic MM was 0.65 [95% confidence interval (CI) 0.48 to 0.87], and in advanced RCC the OR was 0.47 (95% CI 0.26-0.85). In five metastatic MM trials and three RCC trials, enough data on survival were reported to estimate a pooled 1-year OR for survival. The pooled OR for improved survival with IFN-alpha was 0.69 (95% CI 0.50-0.94), and 0.46 (95% CI 0.28-0.75), respectively. The data on both metastatic MM and advanced RCC indicate that better response rates and prolonged survival can be achieved with regimens including IFN-alpha. The clinical relevance of these findings will be discussed.     

Meta-analysis to assess the efficacy of interferon-alpha in patients with follicular non-Hodgkin's lymphoma

The authors wanted to determine whether adding interferon-alpha (IFN-alpha) to chemotherapy regimens, in either induction or maintenance settings, provides additional survival benefits in follicular non-Hodgkin's lymphoma (NHL). A meta-analysis was performed based on published data from randomized controlled clinical trials involving nine separate study populations. Patients receiving IFN-alpha (in either induction or maintenance therapy) had significantly increased 5-year and progression-free survival rates at 3 and 5 years compared with concurrent controls. The advantages of IFN-alpha therapy were most marked in studies using anthracycline-containing induction chemotherapy; in these studies, patients who received IFN-alpha had approximately 20% increased progression-free survival rates compared with controls and a lesser survival advantage. The available literature did not allow a determination of the relative benefit of IFN-alpha in induction or maintenance treatments for NHL or a determination of the optimum duration of IFN-alpha treatment. Although questions remain about its optimal use. IFN-alpha appears to prolong survival time in patients with follicular NHL.     

Endostatin neoadjuvant gene therapy extends survival in an orthotopic metastatic mouse model of renal cell carcinoma

Despite recent advances in targeted therapy, renal cell carcinoma (RCC) remains one of the most lethal urologic malignancies. Approximately 30% of patients with localised RCC will develop metastases after curative surgery. Presurgical therapy has been explored for treatment of localised RCC. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential use of an antiangiogenic agent as a neoadjuvant therapy in an orthotopic metastatic mouse model of RCC. BALB/c mice bearing Renca cells were treated before nephrectomy with NIH/3T3-LendSN cells. At the end of the experiment, ES serum levels were measured. Primary and metastatic tumour area and microvascular area were determined. In the survival studies, mice were monitored daily until they died. ES serum levels in treated mice were higher in the control group (P < 0.05). The median primary tumour area and the mean microvascular area were significantly lower in the ES-treated group compared to control group (P < 0.05). The proliferation of Renca cells in the ES-treated group was significantly reduced compared with the control group (P < 0.01). ES therapy led to a significant reduction in the number of pulmonary metastatic nodules compared with the control group (P < 0.01). Kaplan–Meier survival curves showed that the probability of survival was significantly higher in mice receiving ES therapy (P = 0.0243, Log-Rank test). Our results indicated that neoadjuvant ES gene therapy has the potential to decrease tumour burden, extend survival, and may have clinical benefit in the management of RCC.     

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

ABSTRACT

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC.

Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development.

Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.     

Management of hypertriglyceridemia in patients receiving interferon for malignant melanoma

OBJECTIVE: To describe 3 cases of hypertriglyceridemia associated with the use of interferon alfa (IFN-alpha) for the treatment of malignant melanoma and propose a management plan for dyslipidemia associated with interferon therapy. CASE SUMMARIES: Three case reports of hypertriglyceridemia with or without elevation of total cholesterol level associated with the use of adjuvant IFN-alpha for the treatment of malignant melanoma are described. These patients received IFN-alpha-based adjuvant therapy with doses ranging from 5-20 million units/m(2) for 1-2 years' duration. The onset and severity of dyslipidemia appeared to occur randomly. Pre-existing cardiovascular disorders did not seem to play a role. The patients were treated with atorvastatin, gemfibrozil, and a combination of lovastatin with niacin, depending on their lipid panel results. DISCUSSION: Based on our case reports and published data, hypertriglyceridemia is more frequently associated with longer duration of interferon therapy, although the time of onset is not clearly defined. Presence or absence of baseline dyslipidemia does not seem to play a role in the development of hypertriglyceridemia associated with interferon, and its occurrence and severity are not dependent on the dose. Lifestyle modifications should be encouraged in patients who develop dyslipidemia, and drug treatment should be considered. If drug therapy is indicated, fibric acid derivatives should be considered as first-line therapy. Even at lower doses, this class of drug seems to be effective in managing severe triglyceride elevations in these patients. The Naranjo probability scale of these cases ranged from possible to probable. CONCLUSIONS: Hypertriglyceridemia is a rare but potentially severe adverse consequence of interferon therapy. Patients with malignant melanoma who develop dyslipidemia while receiving interferon should be considered for antidyslipidemic management.     

α干扰素对慢性髓系白血病患者异基因骨髓移植预后的影响

目的了解α干扰素(IFN-α)对慢性髓系白血病(CML)患者异基因骨髓移植(allo-BMT)预后的影响.方法分析总结1993年3月～1999年底行allo-BMT的CML第1次慢性期(CP1)患者85例.BMT前未用IFN-α治疗组30例,用IFN-α治疗55例;其中疗程<6个月30例,6～12个月15例,>12个月10例.结果经COX多元回归分析,患者年龄、性别、确诊至BMT的时间、预处理方案、停IFN距BMT时间对生存率无影响,而用IFN治疗的疗程与生存率有关;4组的植活时间、Ⅱ～Ⅳ度急性移植物抗宿主病(GVHD)、慢性GVHD、肝静脉闭塞症、白血病复发的发生率及非白血病死亡率差异均无显著性.IFN-α用药≥6个月组Ⅲ～Ⅳ度GVHD发生率比其它两组明显升高(P<0.01).与不用IFN-α组及用药>12个月组比较,IFN-α用药<6个月组5年生存率高(P<0.05),而与用药6～12个月组相比,IFN-α疗程<6个月组5年生存率也高,但差异无统计学意义.结论用IFN-α治疗半年以内,5年生存率有提高的趋势,应用半年以上有可能使Ⅲ～Ⅳ度GVHD发生率增加,但应用1年以内,对生存率没有造成不良影响.IFN对CMLallo-BMT预后的影响尚须更多资料进一步证实.     

Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM.

The biological target for interferon (IFN)-alpha in chronic myeloid leukemia (CML) is unknown, but one possibility is that amplification of granulocyte-macrophage colony-forming cells (CFU-GM) is reduced. Replating CFU-GM colonies and observing secondary colony formation provides a measure of CFU-GM amplification. Amplification of CML, but not normal, CFU-GM in vitro was significantly inhibited by IFN-alpha (P = 0.02). In 5 out of 15 CML cases studied by fluorescence in situ hybridization, in vitro treatment with IFN-alpha increased the proportion of CFU-GM, which lacked BCR-ABL. The ability of patients' CFU-GM to amplify, and suppression of this ability by IFN-alpha, predicted responsiveness to IFN-alpha therapy in 86% of cases. Investigation of patients on treatment with IFN-alpha showed a threefold reduction in CFU-GM amplification in responders (P = 0.03) but no significant change in nonresponders (P = 0.8). We conclude that IFN-alpha preferentially suppresses amplification of CML CFU-GM to varying degrees. The differing in vitro sensitivities to IFN-alpha and growth kinetics of individual patients' cells could help differentiate those who will or will not benefit from treatment with IFN-alpha.     

Role of interferon in the treatment of multiple myeloma

A number of clinical trials were conducted to determine the therapeutic efficacy of interferon in multiple myeloma (MM). Small, statistically significant increase in progression-free survival and overall survival of up to 6 months are identified in meta-analysis, most clearly observed for patients receiving maintenance therapy following chemotherapy or autologous stem cell transplantation. However, potential benefits must be balanced against possible toxicity and the financial costs of interferon. Therefore interferon therapy is not recommended during induction therapy. Patients who respond to first-line therapy can be offered interferon as a maintenance therapy, but the strength of this recommendation is low because of the modest clinical benefit, weighed against the frequent side effects.     

Metastatic renal cell carcinoma imaging evaluation in the era of anti-angiogenic therapies

During the last decade, the arsenal of anti-angiogenic (AAG) agents used to treat metastatic renal cell carcinoma (RCC) has grown and revolutionized the treatment of metastatic RCC, leading to improved overall survival compared to conventional chemotherapy and traditional immunotherapy agents. AAG agents include inhibitors of vascular endothelial growth factor receptor signaling pathways and mammalian target of rapamycin inhibitors. Both of these classes of targeted agents are considered cytostatic rather than cytotoxic, inducing tumor stabilization rather than marked tumor shrinkage. As a result, decreases in tumor size alone are often minimal and/or occur late in the course of successful AAG therapy, while tumor devascularization is a distinct feature of AAG therapy. In successful AAG therapy, tumor devascularization manifests on computed tomography images as a composite of a decrease in tumor size, a decrease in tumor attenuation, and the development of tumor necrosis. In this article, we review Response Evaluation Criteria in Solid Tumors (RECIST)—the current standard of care for tumor treatment response assessment which is based merely on changes in tumor length—and its assessment of metastatic RCC tumor response in the era of AAG therapies. We then review the features of an ideal tumor imaging biomarker for predicting metastatic RCC response to a particular AAG agent and serving as a longitudinal tumor response assessment tool. Finally, a discussion of the more recently proposed imaging response criteria and new imaging trends in metastatic RCC response assessment will be reviewed.     

Renal cell carcinoma metastatic to the pancreas: clinical and radiological features

OBJECTIVE: To review the clinical features, computed tomographic (CT) appearance, and treatment outcomes in a case series of patients with renal cell carcinoma (RCC) metastatic to the pancreas. PATIENTS AND METHODS: We retrospectively reviewed the records of 23 patients (15 men and 8 women) with RCC metastatic to the pancreas, detected by CT examination between 1986 and 1996. All patients had undergone a previous nephrectomy for RCC. RESULTS: Isolated mild elevation in liver function test results (in 5 patients) or in serum amylase level (in 8 patients) was observed. New-onset diabetes was detected in 3 patients. The CT characteristics of the pancreatic metastases generally resembled those of primary RCC with well-defined margins and greater enhancement than normal pancreas with a central area of low attenuation. The mean interval between resection of the primary RCC and detection of the pancreatic metastases was 116 months (range, 1-295 months). In 18 patients (78%), the pancreatic metastases were diagnosed more than 5 years after nephrectomy. The pancreas was the initial metastatic site in 12 patients (52%). Survival was shortened with higher tumor grade (mean survival time of 41 months and 10 months in patients with grade 2 and 3, respectively). Surgical resection was carried out in 11 patients (7 distal and 3 total pancreatectomies and 1 distal pancreatectomy followed 4 years later by total pancreatectomy), with 8 patients alive at a mean follow-up of 4 years, 6 of whom remained free of recurrence. Overall, 12 patients (52%) were alive at a mean of 42 months after diagnosis of metastatic disease. CONCLUSIONS: The appearance of metastatic RCC lesions in the pancreas closely resembles the appearance of primary RCC on CT images. Pancreatic metastases from RCC are frequently detected many years after nephrectomy. Patient survival correlates with tumor grade. Histologic analysis of pancreatic masses in patients with a history of resected primary RCC is important since the prognosis for RCC metastatic to the pancreas is much better than that for primary pancreatic adenocarcinoma.     

Expression of CXCR3 on mononuclear cells and CXCR3 ligands in patients with metastatic renal cell carcinoma in response to systemic IL-2 therapy

Chemokines play an important role in regulating tumor-mediated immunity, angiogenesis, and tumor cell metastasis. The chemokine receptor, CXCR3, is expressed in various human tumors, including renal cell carcinoma (RCC). CXCR3 is also associated with antiangiogenic effects in multiple tumors, and we hypothesized that interleukin-2 (IL-2) treatment of patients with metastatic clear cell RCC could augment CXCR3 levels on circulating mononuclear cells and correlate to outcome. The kinetics of CXCR3 expression on circulating mononuclear cells and its ligands (CXCL9, CXCL10, and CXCL11) in plasma were evaluated in 20 patients with metastatic clear cell RCC during cycles 1 and 2 of high dose IL-2 therapy. Subpopulations of peripheral blood mononuclear cells (PBMCs) were studied by dual color flow cytometry. Angiogenic ligands were measured and an "angiogenic ratio" was calculated prehigh and posthigh dose IL-2. CXCR3 expression on PBMC at baseline was similar in patients with metastatic RCC and normal controls. PBMC CXCR3 expression increased during treatment, and peaked during cycle 2. Plasma from RCC patients displayed similar baseline levels of CXCR3 ligands to normal controls. However, the angiogenic ratio was significantly increased in patients with metastatic RCC at baseline. Plasma levels of CXCR3 ligands increased during treatment, resulting in a reversal in the angiogenic ratio to favor angiostatic chemokines. The CXCR3/CXCR3 ligand biologic axis and angiogenic ratio may be important biomarkers in clear cell RCC patients who are undergoing high dose IL-2 therapy.     

Treatment of malignant melanoma.

OBJECTIVE: To review the current treatments for cutaneous melanoma and discuss treatment approaches for each patient population. DATA SOURCES: MEDLINE and IOWA database search from January 1990 to December 1998. DATA EXTRACTION: Clinical trials and review articles were selected and classified to answer questions considered of clinical relevance. RESULTS: Patients with stage I, II, and III melanoma should undergo excision after biopsy. In patients with stage IV melanoma, surgical excision of metastatic melanoma is not considered curative but can provide palliation and improve quality of life. Therapeutic lymph node dissection should be performed in patients with melanoma in stages III and IV once pathologic confirmation is obtained. Patients at high risk for recurrence or metastasis may also be considered for elective node dissection. Adjuvant therapy after surgery excision is not a standard of care in patients with stage I and IIa melanoma. In patients with stage IIb and III melanoma, the best results have been obtained with high doses of interferon alfa-2b, although toxicity is of concern. Isolated limb perfusion with melphalan adjuvant to surgery has demonstrated clinically significant benefit in patients with locally recurrent melanoma and in-transit metastases. Studies comparing efficacy and quality of life with this technique or with high doses of interferon alfa-2b are needed. The technique cannot be recommended for high-risk primary melanoma of an extremity with no clinical evidence of metastatic disease. CONCLUSIONS: To date, dacarbazine still appears to be the treatment of first choice in metastatic melanoma, outside of a clinical trial. The combination of chemotherapy with interferon alfa-2b or interferon alfa-2a enhances toxicity without a significant survival advantage. Aldesleukin may be an alternative in selected patients when other treatments have failed, but the higher toxicity and cost must be considered.     

Depressive symptoms after initiation of interferon therapy in human immunodeficiency virus-infected patients with chronic hepatitis C

BACKGROUND: Interferon alpha (IFN-alpha) therapy for chronic hepatitis C (CHC) infection is commonly associated with neuropsychiatric side effects including depressive symptomatology. In this study, we evaluated the incidence and management of depressive symptoms during IFN-alpha therapy in HIV-infected patients with CHC. METHODS: HIV-infected patients with CHC who began IFN-alpha and ribavirin therapy during the recruitment period April 2001 to April 2003 were included in the study. Patients with a history of major depressive disorder were excluded. RESULTS: Of 113 co-infected patients who started IFN-alpha therapy during the recruitment period, 45 (40%) developed symptoms of depression (sadness, tiredness and apathy). Twenty of them (44%) were treated with citalopram, a selective serotonin re-uptake inhibitor, resulting in a significant improvement in their symptoms. Most of the patients (60%) showed depressive side effects in the first 3 months after initiation of IFN-alpha. In addition, during the study, three patients developed psychotic symptoms and one committed suicide. CONCLUSIONS: The incidence of depressive symptoms in patients with HIV/HCV co-infection treated with IFN-alpha is high. Most of the depressive symptoms were not severe and improved with antidepressant therapy, without reduction or cessation of IFN-alpha therapy. During the first weeks after initiating IFN-alpha therapy for HIV/HCV co-infection, close assessment of psychiatric symptoms is recommended. Early treatment of these side effects with antidepressants would help avoid early dropouts from interferon therapy.     

Duration of therapy in advanced, metastatic non-small-cell lung cancer

Advanced, metastatic non-small-cell lung cancer (NSCLC) remains a challenge to oncologists. There is little doubt that platinum-based combination chemotherapy improves survival and has a palliative effect by improved patients' symptoms and quality of life. Yet chemotherapy is not curative, is associated with toxicity, and can be costly. In most recent phase III trials, the median survival time is 8 to 10 months. Therefore, the optimal duration of therapy-one that balances survival and palliative effects against toxicity, cost, and intrusiveness on patients' lives-remains an important issue. Three recent randomized trials that addressed this in stage IIIB/IV NSCLC are reviewed. Two evaluated brief durations of first-line therapy (3 cycles in one, 4 in the other) versus longer-duration therapy (6 cycles and continuous therapy, respectively). No benefit in response rate, symptom relief, quality of life, or survival was noted for the longer-duration therapy. In addition, cumulative toxicities occurred more frequently in patients who received longer treatment durations. The third trial administered 4 cycles of first-line platinum-based therapy and then randomized responding patients to observation or 6 months of further therapy with vinorelbine. No survival benefit was noted for vinorelbine. There trials suggest that duration of first-line therapy in advanced, metastatic NSCLC should be brief (3 to 4 cycles). Prolonged therapy does not appear to improve survival and carries the risk of cumulative toxicity. Second-line therapy considered in those patients fit enough to receive it at the time of disease progression.     

Phase 1/2 clinical trial of interferon alpha2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma

To evaluate the feasibility, efficacy, and biologic effects of weekly liposome-encapsulated all-trans retinoic acid (ATRA-IV) plus interferon alpha2b (IFN) in patients with advanced renal cell carcinoma (RCC). Twenty-six patients with metastatic RCC were treated on a phase 1/2 trial with weekly ATRA-IV and IFN SQ daily 5 d/wk. Twelve patients received ATRA-IV at three dose levels (60, 75, and 90 mg/m2) according to phase 1 methodology, and 14 additional patients received 90 mg/m2. Response was assessed according to an intention-to-treat analysis. Serum retinoic acid (RA) concentrations were assayed and peripheral blood mononuclear cell mRNA expression of RA and IFN-inducible genes (RARalpha, RARbeta2, IRF1, CRABP2, and TRAIL) were examined. No dose limiting toxicities occurred at 60 mg/m2; grade 3 leukopenia affected 1/6 patients at 75 mg/m2, whereas 3 patients received 90 mg/m2 without a dose limiting toxicities. Fourteen additional patients received 90 mg/m2 ATRA-IV without grade 3/4 toxicity. Five of 26 (19%) patients achieved a major response, with a median duration of 14 months (range 9 to 23); 9 additional patients (41%) demonstrated stable disease or minor response lasting > or =4 months. No significant differences in serum (RA) after ATRA infusion were detected between weeks 1 and 8 of treatment. Peripheral blood mononuclear cell mRNA expression did not correlate with clinical response. The addition of weekly ATRA-IV to IFN therapy is feasible and well tolerated, resulting in sustainable increased serum (RA). This regimen demonstrates antitumor activity in metastatic RCC, and suggests ATRA-IV augments IFN therapy.     

Molecular analysis of resistance to interferon in patients with laryngeal papillomatosis.

Although interferon (IFN)-alpha has been used successfully as an adjuvant therapy in laryngeal papillomatosis, some patients are resistant to this treatment. In order to know which patients will benefit from the therapy, we have tried to find a relationship between the IFN response and the viral and host parameters in the lesion. Detection of viral type and copy numbers by polymerase chain reaction (PCR) showed that all patients infected with human papillomavirus (HPV)-11 were sensitive to the treatment, in contrast to those infected with HPV-6. These differences could be explained in part by the inability of HPV-11 E7 to inhibit the induction of an IFN-responsive element, whereas HPV-6 E7 almost completely inhibited the activity of this promoter in transient transfection experiments. Local immune status in the lesion showed that all HPV-11-infected patients had detectable levels of interleukin (IL)-15 and IFN-gamma mRNA, in contrast to HPV-6-infected patients, in whom mRNA for these cytokines was almost absent. Viral copy numbers and levels of IL-4 mRNA could not be correlated with IFN response. Only one patient resistant to recombinant IFN-alpha2b and negative for HPV DNA presented high titers of neutralizing anti-IFN-alpha2b antibodies. This patient became sensitive when natural IFN-alpha was administered. These results suggest that response to IFN may be a complex phenomenon resulting from the interaction between viral and host elements.     

Adenovirus-mediated gene transfer of interferon alpha improves dimethylnitrosamine-induced liver cirrhosis in rat model

Several lines of evidence suggest that interferon (IFN)-alpha is effective in suppression of liver cirrhosis (LC) as well as hepatitis C virus (HCV) infection, which is a major cause of LC in Japan. However, IFN-alpha often causes systemic toxicity such as flu-like symptoms, which precludes the IFN-alpha dose escalation required for clinical efficacy. Since IFN-alpha is rapidly degraded in the blood circulation, only a small amount of subcutaneously injected IFN-alpha protein can reach the target organ, the liver. It is expected that on-site IFN-alpha production in the liver overcomes the limitation of the conventional parenteral IFN-alpha administration. An adenovirus vector expressing the rat IFN-alpha gene (AxCA-rIFN) was injected intravenously into rats with dimethylnitrosamine-induced LC. While the subcutaneous IFN-alpha protein injection led to a transient elevation of the cytokine both in the liver and serum, the vector-mediated IFN-alpha gene transduction induced a significant amount of IFN-alpha detected in the liver but not in the serum. The injection of AxCA-rIFN prevented the progression of the rat LC, and improved the survival rate of the treated rats. Although no significant toxicity was noted in the animals, we showed that IFN-alpha gene expression in the liver can be efficiently downregulated by the Cre/loxP-mediated shut-off system, in case the IFN-alpha overdose becomes a problem. The study suggested for the first time the advantage and feasibility of IFN-alpha gene therapy for LC.     

Inhibition of lung metastases of murine renal cell carcinoma by the combination of radiation and interferon-alpha-producing tumor cell vaccine

We have previously demonstrated in a murine lung metastasis model that local sublethal radiation of tumors can synergistically enhance their sensitivity to immunotherapy with either systemic high-dose interleukin-2 (IL-2) or vaccination with autologous tumor cells expressing IL-2, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF). Host antitumor activity was mediated in large part by natural killer cells, which can be activated by IFN-alpha. In the present study, we used this lung metastasis model to investigate the efficacy of combined therapy with local tumor radiation and vaccination with IFN-alpha-secreting tumor cells (Renca/IFN-alpha). The in vitro and in vivo growth rates of Renca/IFN-alpha cells were significantly reduced relative to normal controls. Subcutaneous vaccination with Renca/IFN-alpha or selective X-irradiation of the left lung (300 rad) reduced the number of lung tumors by 40% and 27%, respectively. The combination of lung irradiation plus vaccination reduced the number of lung metastases by 60%, and the net tumor volume by 95%. The reductions in tumor volume in both irradiated and non-irradiated lungs were comparable. These results indicate that host antitumor response to subcutaneous vaccination with Renca/IFN-alpha was systemic, and was significantly enhanced by radiation of tumor-bearing lungs. A regimen based on enhancement of IFN-alpha immunotherapy by local tumor radiation may be useful in the treatment of metastatic renal cell carcinoma.     

Effect of alpha interferon (IFN-alpha) on 2'-5' oligoadenylate synthetase activity in peripheral blood mononuclear cells of patients with chronic hepatitis C: relationship to the antiviral effect of IFN-alpha.

Alpha interferon (IFN-alpha) is, to date, the only treatment with proven efficacy in patients with chronic hepatitis C. However, less than 15% of the patients have a sustained response to IFN-alpha. Interferon acts through the induction of various cellular enzymes. Among them, the 2'-5' oligoadenylate synthetase (2-5OAS) is (at least in part) responsible for a direct antiviral effect of IFN-alpha. The aim of this study was to determine whether basal and IFN-alpha-induced in vivo and in vitro 2-5OAS activities measured in peripheral blood mononuclear cells predict biochemical and virological responses to IFN-alpha in patients with chronic hepatitis C. 2-5OAS activity in peripheral blood mononuclear cells and the antiviral effect of IFN-alpha were studied in 36 patients with chronic hepatitis C (27 men and 9 women; mean age, 44.7 years). Basal in vivo 2-5OAS activity (mean +/- standard error of the mean) was 4.41 +/- 0.69 nmol/10(6) cells. It was significantly induced at month 3 of IFN-alpha therapy (18.07 +/- 2.74 nmol/10(6) cells; P = 0.0001). No significant differences were found in basal in vivo 2-5OAS activities, in IFN-alpha-induced/basal in vitro 2-5OAS activity ratios, in IFN-alpha-induced in vivo 2-5OAS activities, and in IFN-alpha-induced/basal in vivo 2-5OAS activity ratios between the patients with and without a biochemical response (normal alanine aminotransferase activity in serum) or a virological response (normal alanine aminotransferase activity in serum and negative hepatitis C virus RNA detection) at any step of the study. At month 3 of therapy, p69, which is considered to be the active isoform of 2-5OAS, was induced, as demonstrated by Western blot (immunoblot) analysis in 50% of the patients, and induction of the p100 isoform was observed in 70% of the patients. No significant relationship with the response to IFN-alpha therapy was observed. Our results suggest that a deficiency of the IFN-alpha-dependent 2-5OAS system, which could be genetically determined, is unlikely to be responsible for the failure to achieve biochemical and virological responses to IFN-alpha therapy in patients with chronic hepatitis C.     

Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma

OBJECTIVE: This study was aimed at evaluating the effects of interferon (IFN)-alpha on survival rate after resection of hepatocellular carcinoma. METHODS: In a randomized, controlled trial by the University Hospital, Medical Center and affiliated hospital in Osaka, Japan, 30 men were after surgery randomly allocated to an IFN-alpha group (15 patients) and to a control group. Patients in the IFN group received 6 MIU of IFN-alpha intramuscularly daily for 2 weeks, then three times a week for 14 weeks, and finally twice a week for 88 weeks. The incidence of recurrence and survival rate were then studied. RESULTS: The response to IFN was sustained viral response (SVR) in 2 patients, biochemical response (BR) in 6, partial response (PR) in 5, and no response (NR) in 2. In the control, 8 of the 15 patients demonstrated continuous abnormally high levels of ALT. At the end point of the study, intrahepatic recurrence was detected in 9 of the IFN group and in 13 of the control (p = 0.065, log-rank test). The cumulative survival rate was higher in the IFN group than in the controls (p = 0.041). CONCLUSION: Postoperative IFN therapy improves the outcome after resection of hepatitis C virus-related hepatocellular carcinoma.