Cytokine-based Therapies Research Articles

A Proinflammatory Role for Interleukin-22 in the Immune Response to Hepatitis B Virus

T-helper (Th)17 cells that secrete interleukin (IL)-22 have immunomodulatory and protective properties in the liver and other tissues. IL-22 induces expression of proinflammatory genes but is also mitogenic and antiapoptotic in hepatocytes. Therefore, it could have multiple functions in the immune response to hepatitis B virus (HBV). We examined the role of IL-22 in regulating liver inflammation in HBV transgenic mice and measured levels of IL-22 in HBV-infected patients. In HBV transgenic mice, injection of a single dose of IL-22 increased hepatic expression of proinflammatory genes but did not directly inhibit virus replication. When splenocytes from HBV-immunized mice were transferred into HBV transgenic mice, the severity of the subsequent liver damage was ameliorated by neutralization of IL-22. In this model, IL-22 depletion did not affect interferon gamma-mediated noncytopathic inhibition of virus replication initiated by HBV-specific cytotoxic T cells, but it significantly inhibited recruitment of antigen-nonspecific inflammatory cells into the liver. In patients with acute HBV infections, the percentage of Th17 cells in peripheral blood and concentration of IL-22 in serum were significantly increased. IL-22 appears to be an important mediator of the inflammatory response following recognition of HBV by T cells in the liver. These findings might be relevant to the development of cytokine-based therapies for patients with HBV infection.

Pilot trial of interleukin-2 and zoledronic acid to augment γδ T cells as treatment for patients with refractory renal cell carcinoma

Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9Vδ2 T cell in patients with metastatic RCC.

Effects of Combination of Proliferative Agents and Erythropoietin on Left Ventricular Remodeling Post–Myocardial Infarction

Erythropoietin (EPO) has the potential to improve ischemic tissue by mobilizing endothelial progenitor cells and enhancing neovascularization. We hypothesized that combining EPO with human chorionic gonadotrophin (hCG) would improve post-myocardial infarction (MI) effects synergistically. After MI, five to seven animals were randomly assigned to each of the following treatments: control; hCG; EPO; hCG + EPO, and prolactin (PRL) + EPO. Follow-up echocardiograms were performed to assess cardiac structure and function. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and western blot analysis for apoptosis-related proteins, and cell proliferation by immunostaining for Ki67 and c-kit cells. The MI-mediated increased chamber systolic dimension (p < 0.05 in controls) was attenuated by hCG, EPO, and hCG + EPO (p < 0.05 vs. control) but not PRL + EPO. Similarly all treatment groups, except PRL + EPO, reduced MI-induced increases (p < 0.05 vs. control) in ejection fraction (EF). The functional improvement in the EPO-treated groups was accompanied by increased capillary density. Apoptosis was markedly reduced in all treated groups. Significantly more cardiac c-kit(+) cells were found in the hCG + EPO group. Our findings revealed that EPO, hCG, or their combination ameliorate cardiac remodeling post-MI. Whereas EPO stimulates neovascularization only and hCG + EPO stimulates c-kit+ cell proliferation. These data suggest that combining mobilizing and proliferative agents adds to the durability and sustainability of cytokine-based therapies for remodeling post-MI.

6 First and further lines of therapy in clear cell renal cell carcinoma

Until the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC).This review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms.Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature.Targeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF)–targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first- and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed.Increasing clinical evidence is clarifying appropriate first- and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials.

Cytokine Therapies in Crohns Disease: Where are We Now and where should We Go?

In the gut of patients with Crohn's disease (CD), one of the major forms of inflammatory bowel diseases in humans, distinct subsets of T helper (Th) cells produce large amounts of cytokines, which are supposed to orchestrate the immuno-inflammatory process leading to the tissue damage. Indeed, cytokine blockers, including the three licensed anti-TNF-alpha and the neutralizing IL-12/p40 antibodies, have already been tested with success in CD. More than one third of patients do not respond to these treatments and response can wane with time. Moreover, blockade of such cytokines has been reported to associate with development of severe side effects and/or new immune-mediated pathologies. These findings and our better understanding of cytokine-associated effector pathways of tissue destruction suggest the necessity of novel cytokine-based therapies in CD.

Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies.

Fatigue is one of the most common symptoms associated with cancer. Persistent fatigue can impair multiple aspects of daily functioning and quality of life, and patients report that treatment-related fatigue has a greater impact than other symptoms, including pain, nausea, and depression. Thus, management of fatigue is recognized as an important component of care for patients with cancer. Treatment of advanced and metastatic renal cell carcinoma (RCC) was, until recently, limited to cytokine-based therapies, which are associated with modest response rates and significant toxicity, including high rates of treatment-related fatigue. The paradigm for RCC treatment has shifted dramatically in the last 5 years with the advent of efficacious targeted therapies. These agents provide the promise of better tolerability because of their more selective mechanisms of action. However, there is considerable variation in the selectivity of targeted agents for RCC, and a review of randomized clinical trials in patients with advanced and/or metastatic disease reveals that there is considerable variation in the tolerability of these agents. Fatigue remains a prominent toxicity with current targeted therapies. Future agents that show better selectivity and potency than current targeted therapies should help to provide better efficacy and tolerability.

PL4-2 Cytokine-based therapies in HIV infection: Lessons from IL-2 and expectations from IL-7

PL4-2 Cytokine-based therapies in HIV infection: Lessons from IL-2 and expectations from IL-7

Interleukin (IL)-21, but not IL-2, induces antiviral activity and costimulatory molecules in CD8 T cells without promoting HIV replication (42.15)

Abstract Background: Chronic HIV infection is marked by defective cytotoxic T cell (CTL) effector function, skewed terminally-differentiated profile, and reduced expression of the costimulatory molecules CD27 and CD28. Incubation ex vivo of CTL from HIV infected persons with IL-21 augments cytotoxic effector molecules and function. In this study we analyzed IL-21 effects on CTL as compared to IL-2. Methods: Purified CD8 T cells from healthy donors were pre-activated with αCD3+αCD28 and cultured with IL-21 or IL-2 for 6 days. Phenotype and effector function were evaluated by flow cytometry, gene expression by real-time PCR, effect on HIV replication with the reporter cell line TZM-bl. Results: IL-21 induced higher CTL degranulation in response to TCR stimulation, as compared to IL-2. Co-culture of IL-21-treated CTL with autologous HIV infected CD4 T cells reduced HIV replication. Importantly, IL-21 did not induce viral replication when added to HIV infected CD4 T cells. Furthermore, TCR-activated CTL upreglated CD27 and CD28 and acquired a central memory phenotype when incubated with IL-21, but not with IL-2. IL-21 also selectively induced Bcl6, key transcription factor for memory T cells. Conclusions: Since IL-21 enhances CTL antiviral activity, promotes a central memory phenotype and induces costimulatory molecules, this cytokine has an appealing immunomodulatory profile and merits further consideration for cytokine-based therapies, alone or in combination with antiretroviral drugs.

An Overview of Cytokines and Cytokine Antagonists as Therapeutic Agents

Cytokine-based therapies have the potential to provide novel treatments for cancer, autoimmune diseases, and many types of infectious disease. However, to date, the full clinical potential of cytokines as drugs has been limited by a number of factors. To discuss these limitations and explore ways to overcome them, the FDA partnered with the New York Academy of Sciences in March 2009 to host a two-day forum to discuss more effective ways to harness the clinical potential of cytokines and cytokine antagonists as therapeutic agents. The first day was focused primarily on the use of recombinant cytokines as therapeutic agents for treatment of human diseases. The second day focused largely on the use of cytokine antagonists as therapeutic agents for treatment of human diseases. This issue of the Annals includes more than a dozen papers that summarize much of the information that was presented during this very informative two-day conference.

Treatment Algorithms in Metastatic Renal Cell Carcinoma, Including the Potential Role of the Novel Oral Mammalian Target of Rapamycin Inhibitor Everolimus

Abstract Context Few treatment options were available for metastatic renal cell carcinoma (mRCC) until the development of novel targeted agents directed against angiogenesis and tumour growth. Objective This review discusses current targeted therapies for mRCC and outlines the position of everolimus, a novel, orally administered inhibitor of the mammalian target of rapamycin (mTOR), in current treatment algorithms. Evidence acquisition Medical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature. Evidence synthesis Targeted treatment for mRCC can be categorised for the following patient groups: previously untreated patients, those refractory to immunotherapy or chemotherapy, and those refractory to vascular endothelial growth factor (VEGF)–targeted therapy. Sunitinib and bevacizumab (combined with interferon alfa) are generally considered first-line treatment options in patients with favourable or intermediate prognosis. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, one recommendation is to switch to an agent with a different mechanism of action or molecular target, for example, an mTOR inhibitor. Everolimus (RAD001) has shown promising efficacy in the first phase 3 clinical trial in patients with mRCC with favourable, intermediate, and poor risk whose disease had progressed on VEGF-targeted therapy. Conclusions Increasing clinical evidence is clarifying appropriate first- and second-line treatment with targeted agents for patients with mRCC. Based on good results of published phase 3 clinical data, the potential use of everolimus in the second-line setting has been recognised in recent (2008 and 2009) guidelines, including those of the European Society of Medical Oncology, the European Association of Urology, the European Organisation for Research and Treatment of Cancer Genitourinary Group, the Spanish Oncology Genitourinary Group, the French Urology Association, the UK consensus guidelines, the National Comprehensive Cancer Network (United States), and Cancer Care Ontario (Canada).

Current Immunotherapy for Solid Tumors

Explorative knowledge of cellular and molecular mechanisms of immune function and regulation has provided optimism in developing cancer immunotherapy. However, three decades of experimental and clinical investigations to offer powerful immunotherapeutic strategies against solid tumors, with the possible exception of monoclonal antibody-targeted therapies, have not succeeded in significantly prolonging patient survival. Nonspecific immune approaches, including cytokine-based therapies and allogeneic hematopoietic stem cell transplantation, have so far produced consistent, although limited, results. In this review, we present the developments of cell transfer-based strategies that, in preclinical studies, have demonstrated potential efficacy, but have only established tumor regression in limited numbers of patients. The key to success demands creative combinations of tumor antigens, adjuvance, gene modification and various administration strategies in the development of cell-based therapies together with other cancer-treatment principles, often in a stepwise 'space-rocket-type' approach. Combined efforts of several scientific disciplines, such as tumor biology and immunology, as well as cell and gene research in transplantation, will open new venues. New regulation for clinical trials with advanced therapy medicine products to ensure patient safety will be highlighted.

Cytokines as Immunomodulators in Tuberculosis Therapy

The use of cytokines for therapeutic purposes is limited by their high cost and toxicity. Nevertheless, the emergence of extensively drug-resistant tuberculosis (XDR TB), for which chemotherapy is ineffective, has again made cytokine-based therapy attractive as one of the last available options. The results of clinical trials treating pulmonary tuberculosis with cytokines have not been encouraging, making it clear that therapeutic strategies utilizing a single cytokine are inadequate. To develop effective cytokine-based XDR TB therapies, more basic research will be needed to achieve a better understanding of how cytokines promote a successful immune response. We not only have to investigate cytokines already known to participate in tuberculosis, but also the role of other cytokines and chemokines that may enhance both the mycobacterial killing activity of effector cells and the restriction of bacterial intracellular multiplication. There are already several patents involving cytokines for therapeutic use, in the hope of stimulating the immune system in a variety of infectious diseases, including tuberculosis. The validity of these patents needs to be reassessed from a clinical standpoint, and new applications of patents concerning cytokines potentially useful in XDR TB treatment should be encouraged.

Fractional Polynomials in a New Metastatic Renal Carcinoma Continuous Prognostic Index Involving Histology, Laboratory, and Clinical Predictors

We analyzed the effect of histology and various clinical and laboratory predictors in a new continuous prognostic index for metastatic renal-cell carcinoma based on fractional polynomials. We evaluated 322 metastatic renal-cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. We evaluated papillary histology, along with age, disease localizations, C-reactive protein, and neutrophil count in a new prognostic index, which was based on the multivariable fractional polynomial (MFP) algorithm. The MFP model allowed us to divide patients into three risk groups, using seven selected significant prognostic factors: histology, neutrophils, C-reactive protein, bone metastases, liver metastases, lymph node metastases, and age. Using the multivariable fractional polynomial model, median overall survival for high-, intermediate-, and low-risk patients was 10 months (n=80), 23 months (n=162), and 41 months (n=80) (scheme A; p <or= 0.01), or 7.9 months (n=16), 20 months (n=226), and 41 months (n=80) (scheme B; p <or= 0.001), respectively. Histology, clinical, and laboratory predictors contribute to a MFP algorithm-based prognostic index, allowing for a highly effective long-term risk discrimination in metastatic renal-cell carcinoma patients receiving recombinant immunotherapy. The flexibility in creating patient groups by using a continuous prognostic index allows to meet clinical needs in terms of improved prediction and optimized treatment selection.

Cytokine Therapy for Crohn's Disease: Advances in Translational Research

Crohn's disease (CD) and ulcerative colitis (UC), the two idiopathic inflammatory bowel diseases (IBDs), affect almost two million individuals in North America and several million worldwide. Cytokines are important in the pathogenesis of CD, and their manipulation has successfully reduced disease severity and maintained remission. Following the discovery of novel cytokines and the role they may play in gut mucosal immunity, as well as the emergence of new concepts and changing paradigms in CD pathogenesis, the roles of several cytokines have been elucidated and tested in both preclinical animal models and clinical trials of patients with IBD. Complementary to this, proof of concept for new cytokine targets is rapidly developing, with the possibility of future cytokine-based therapies that may offer greater specificity and decreased toxicity for the treatment of CD. This review discusses novel concepts in CD pathogenesis and the roles of cytokines in the initiation and perpetuation of disease. In addition, we review applications of cytokine-based therapies in human clinical trials and preclinical animal studies. Finally, we discuss novel cytokine targets not yet investigated in vivo and describe their potential contribution to CD pathogenesis.

An approach to estimating prognosis using fractional polynomials in metastatic renal carcinoma

We present a prognostic model for metastatic renal cell carcinoma based on fractional polynomials. We retrospectively analysed 425 metastatic renal cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. In our approach, we categorised a continuous prognostic index produced by the multivariable fractional polynomial (MFP) algorithm, using a strategy in which continuous predictors are kept continuous. The MFP algorithm selected five prognostic factors as significant at the 5% level in a multivariable model: lymph node metastases, liver metastases, bone metastases, age, C-reactive protein and neutrophils. The MFP model allowed us to divide patients into four risk groups achieving median overall survivals of 38 months (low risk), 23 months (low intermediate risk), 15 months (high intermediate risk) and 5.6 months (high risk). Our approach, based on categorising a continuous prognostic index produced by the MFP algorithm, allowed more flexibility in the determination of risk groups than traditional approaches.

Immunotherapy of renal cell carcinoma.

Carcinomas of the kidney generally have a poor prognosis and respond minimally to classical radiotherapy or chemotherapy. Immunotherapy constitutes an interesting alternative to these established forms of treatment, and indeed, cytokine-based therapies have been used for many years, leading to favorable clinical responses in a small subset of patients. During the past few years, immunotherapeutical trials targeting renal cell tumor-associated antigens have also been reported, with diverse passive or active approaches using antibodies or aimed at activating tumor-directed T lymphocytes. The following review presents the results and the progress made in the field, including classical cytokine treatments, non-myeloablative stem cell transplantation and antigen specific-based trials, with special focus on T-cell studies. In consideration of the few specific molecular targets described so far for this tumor entity, current strategies which can lead to the identification of new relevant antigens will be discussed. Hopefully these will very soon contribute to an improvement in renal cell carcinoma specific immunotherapy and its evaluation.

Cytokine pharmacogenetics

Genetic variation plays a significant role in the normal functioning of the immune system, and also in the interaction between many common drugs and cellular pathways. With a growing number of cytokine-based therapies now in mainstream clinical use, the prospect of targeting these agents to the individuals likely to benefit from them most is an appealing one. This review outlines the potential clinical impact of cytokine pharmacogenetics in targeting these therapies to individuals with favourable genetic profiles. The use of such approaches may have important pharmacoeconomic benefits and lead to improved therapeutic profiles for these treatments.

Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever

The aim of this article is to summarize recent clinical, genetic and pathophysiologic findings of familial Mediterranean fever and several of the other systemic autoinflammatory diseases, a recently recognized group of disorders characterized by seemingly unprovoked inflammation but lacking high-titer autoantibodies. Genetic and clinical tools are improving the ability of the clinician to better approach patients with periodic fever and inflammation. The spectrum of reported genetic mutations and susceptible ethnicities for the hereditary periodic fever subset of the autoinflammatory diseases has continued to expand. At the same time, the pathogeneses of many of these diseases are now understood to involve different aspects of a common pathway, largely affecting inflammatory cascades related to IL-1 or tumor necrosis factor-alpha. Three of these diseases which have been grouped as the cryopyrin-associated periodic syndromes result from defects in the same gene, and all three appear to respond well to anti-IL-1 therapy although controlled trials are still in progress. In addition, cytokine-based therapies are also now under investigation for hyperimmunoglobulinemia D with periodic fever syndrome and pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome. The identification of the genes and proteins mutated in many of the autoinflammatory diseases has broadened our understanding of the regulation of inflammation and the immune system, and provided the basis for the use of targeted therapies in these syndromes. We propose an algorithm for the evaluation of a patient with periodic fever, taking into account the patient's age, ethnicity, symptoms and signs, and results from laboratory and genetic testing.

Chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) in psoriasis

Insights into the pathogenesis of psoriasis have provided opportunities to target key steps in the disease process. Tumor necrosis factor-alpha (TNF- alpha) being crucial to the pathogenesis of psoriasis, monoclonal antibodies against this cytokine have proved useful in its treatment. To study the efficacy of chimeric monoclonal antibody to TNF- alpha (infliximab) in Indian patients with recalcitrant psoriasis vulgaris. Three patients with recalcitrant psoriasis vulgaris were studied. Baseline haemogram, biochemical parameters, chest radiograph and Mantoux skin test were performed. A loading dose regimen of 5 mg/kg infliximab was administered at weeks 0, 2 and 6. PASI assessment, adverse drug event monitoring and laboratory assessments were carried out at 2-week intervals until week 10. Patients were followed up until week 22 for relapse. Infliximab was well tolerated. The mean PASI was 25.4 at presentation and declined to 5.5 at 10 weeks. PASI 75 was attained at a mean of 9.6 weeks. Relapse occurred at a mean of 18.6 weeks after the first infusion. This study on Indian patients brings out the importance of cytokine-based therapies in psoriasis. Indigenous production could make these therapies a viable therapeutic option for psoriasis patients in the near future.

Cytokine-Based Therapies for Crohn's Disease — New Paradigms

Crohn's disease is one of two idiopathic inflammatory bowel diseases that affect approximately 1 million people in North America. Despite important advances in diagnosis and treatment in recent years, the underlying cause of the disease remains unclear. As a result, the available therapies are not curative and may pose a substantial risk of side effects. A current theory regarding the pathogenesis of Crohn's disease suggests that there is an overly aggressive immune response against commensal bacteria in a genetically predisposed person. In this context, the activation of lymphocytes and the overexpression of inflammatory cytokines represent a common effector mechanism leading . . .