Seminars in oncology
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Seminars in oncology · Oct 2010
ReviewUpdate on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management.
Immune-modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen-presenting cells and T lymphocytes as an immune response is strongly affected by anti-CD152 (cytotoxic T-lymphocyte antigen-4, CTLA-4)-antibodies. However, specific CTLA-4 antibodies can block the CTLA-4 receptor and thus induce an unrestrained T-cell activation. ⋯ The results of a phase III trial in patients with advanced disease treated with ipilimumab alone or in combination with a peptide vaccination (gp100) recently presented at the 2010 annual meeting of the Ameircan Society of Clinical Oncology (ASCO) made groundbreaking news as ipilimumab was demonstrated to be the first drug in melanoma treatment to show a significant prolongation of survival time. Patients undergoing treatment with CTLA-4 antibodies may experience immune-related phenomena and adverse events (irAEs) that differ greatly from the well-known adverse events of cytotoxic drugs and which are due to the CTLA-4 antibodies' specific mode of action. This review gives a condensed overview on the mechanisms of action, an update on clinical data of the two CTLA-4 antibodies, ipilimumab and tremelimumab, and detailed recommendations for adverse event management strategies.
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Seminars in oncology · Oct 2010
ReviewClinical development of the anti-CTLA-4 antibody tremelimumab.
Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. ⋯ Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4-mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.
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Seminars in oncology · Aug 2010
ReviewDrug development for cancer chemoprevention: focus on molecular targets.
With biomolecular evidence accumulating at an exponential rate, there will be a surge in the development of targeted cancer prevention drugs and interventions in the next decade. Promising results from clinical treatment trials identify a spectrum of targeted cancer therapies in several broad categories. These include both small molecule inhibitors of either key receptors or enzyme binding sites, as well as intravenously delivered monoclonal antibodies that block a specific binding interaction between ligands and their receptors. ⋯ The complementarities of target-related processes within tumors cells, in the tumor microenvironment, and beyond suggests that there is great potential for multi-targeted approaches that may be more effective than single agents and also less prone to resistance. Additional options, related to drug dose and schedule, remain to be established. As long as multiple agents can be used in combination for optimal effect with acceptable toxicity, the co-targeting of the epithelial cell compartment along with other compartments of oncogenic activity is expected to expand the dimensions of targeted prevention and enhance the overall opportunity to eliminate precancer or cells at risk of eventually transitioning to invasive cancer.
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Seminars in oncology · Apr 2010
Recruitment of adolescents and young adults to cancer clinical trials--international comparisons, barriers, and implications.
The last 30 years have seen significant improvements in survival rates for children and older adults. In contrast, the 5-year survival rate among 20 to 39 year olds has been static at around 70% since 1986. Data from the United States, Australia, Italy, and the United Kingdom suggest that this age group also has the lowest rate of clinical trial participation. ⋯ This level of trial activity may be associated with the lack of improvement in survival for the older age group. Strategies to increase the numbers of adolescents and young adults (AYA) recruited to cancer clinical trials have become a focus of research activity in several countries. This article explores possible barriers to recruitment of AYA and summarizes current policies in the United States and the United Kingdom to increase accrual of young adults with cancer to clinical trials.