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Guildford, United Kingdom

Agarwala S.S.,St Lukes Cancer Center
Expert Review of Anticancer Therapy | Year: 2012

For patients with localized melanoma, excision of the primary tumor, including lymphadenectomy for nodal metastases, is standard treatment. However, patients with large primary tumors (stage IIB and IIC) or stage III melanoma have a relatively poor prognosis owing to the high risk of recurrence. High-dose IFN-α2b and pegylated IFN-α2b (PEG-IFN-α2b) are the only approved options for adjuvant therapy of stage III melanoma, but the lack of comparative data has led to considerable confusion in choosing between these options. In this article, current evidence regarding the pharmacokinetics, efficacy, safety and tolerability of adjuvant PEG-IFN-α2b in patients with melanoma is reviewed, with frequent reference to and comparisons with data using IFN-α2b. Particular focus is given to the pharmacokinetic differences between IFN-α2b and PEG-IFN-α2b and their implications for the treatment of high-risk patients. In addition, emerging evidence suggests that PEG-IFN-α2b therapy may provide clinically significant overall survival benefit for selected high-risk patients. © 2012 2012 Expert Reviews Ltd. Source

The successful management of advanced melanoma remains an unmet need because of a resolutely poor prognosis and therapeutic options with limited effectiveness. Dacarbazine and fotemustine are the only approved chemotherapeutic agents for advanced melanoma, yet neither alone or in combination regimens has been shown to extend survival in randomized clinical trials. The only agent to be approved for advanced melanoma in the US in more than 30 years is high-dose bolus interleukin-2, but its use is associated with high toxicity and cost, and it has also failed to show a survival benefit. Our expanding knowledge of the complex factors and pathways regulating immune function has led to the advent of novel immunotherapeutic agents. Among these are ipilimumab and tremelimumab -fully human, monoclonal antibodies directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). The pivotal role of CTLA-4 in regulating T-cell function is established, and a series of preclinical studies provided proof-of-concept evidence of the antitumor activity of anti-CLTA-4 antibodies in combination with vaccines or chemotherapy. Subsequently, anti-CTLA-4 antibodies have shown encouraging results in clinical trials in advanced melanoma. Recent progress in the understanding of melanoma genetics and tumorigenesis has led to potential new therapeutic targets. Molecular targeted agents that inhibit the proliferation and survival of metastatic melanoma cells offer potential partners for anti-CTLA-4 antibodies in combined modality regimens. Novel combinations are reviewed in the context of creating an immunosupportive environment in the host. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Agarwala S.S.,St Lukes Cancer Center | Ribas A.,Jonsson Comprehensive Cancer Center
Journal of Immunotherapy | Year: 2010

Monoclonal antibodies (mAbs) specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA4) are a novel form of immunotherapy for treatment of patients with advanced cancers. These anti-CTLA4mAbs prevent normal downregulation of the immune system, thus prolonging and enhancing T-cell activation and potentially promoting an antitumor immune response. Clinical studies in patients with advanced cancers have indicated that CTLA4 blockade with mAbs is associated with antitumor activity in a small percentage of patients and has a manageable toxicity profile. The key limitations for broader applicability of this mode of therapy are better definition of the mechanism that leads to tumor rejection and the validation of favorable observations in single-arm studies into prospectively randomized clinical trials. Copyright © 2010 by Lippincott Williams & Wilkins. Source

Khelwatty S.A.,Kingston University | Essapen S.,St Lukes Cancer Center | Seddon A.M.,Kingston University | Modjtahedi H.,Kingston University
Frontiers in Bioscience | Year: 2013

Colorectal cancer is one of the leading causes of cancer deaths. At present, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) cetuximab and panitumumab and anti-vascular endothelial growth factor (VEGF) mAb bevacizumab have been incorporated into treatment paradigms for patients with refractory metastatic colorectal cancer. However, many patients simply do not respond to these treatments or eventually acquire resistance following a short course therapy. In this article, we review the literature for studies on the expression patterns, prognostic significance and predictive value of HER (also called erbB) family members and other factors for response to therapy with the HER inhibitors in colorectal cancer. We discuss some of the advances, challenges as well as future opportunities for more effective targeting of the HER receptors using a cocktail of HER inhibitors (e.g. dual and pan HER TKIs, monospecific or bispecific antibodies) in combination with other therapeutic interventions. Source

Fecher L.A.,University of Pennsylvania | Agarwala S.S.,St Lukes Cancer Center | Stephen Hodi F.,Dana-Farber Cancer Institute | Weber J.S.,H. Lee Moffitt Cancer Center and Research Institute
Oncologist | Year: 2013

The treatment for metastatic melanoma has evolved significantly in the past few years. Ipilimumab, an immunotherapy, is now in mainstream oncology practice given that it has shown improved overall survival in randomized clinical trials. Other immune modulating agents, such as programmed death receptor-1 and programmed death receptor ligand-1 antibodies, are showing promise in early clinical trials. This manuscript will review ipilimumab and its most common side effects. Immune-related adverse events (irAEs) are important to recognize early,andtheir presentation, timing of onset,and general recommendations for workup and management will be reviewed. Assembling a multidisciplinary team, as well as thorough education of the patient, is recommended to optimize patient care. ©AlphaMed Press 2013. Source

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