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Malignant Mesothelioma Treatment:

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself. Copyright 2002 by W.B. Saunders Company.

Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity. Cancer Res. 2001 Aug 15;61(16):6201-12.

Odaka M, Sterman DH, Wiewrodt R, Zhang Y, Kiefer M, Amin KM, Gao GP, Wilson JM, Barsoum J, Kaiser LR, Albelda SM. Thoracic Oncology Research Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.

Malignant mesothelioma remains an incurable disease for which immune-modulatory therapies, such as exogenous cytokines, have shown some promise. One such cytokine, IFN-beta, has potent antiproliferative and immunostimulatory activity in vitro, but its in vivo use has been limited by toxicity. We thus conducted studies evaluating intracavitary delivery of a replication-deficient adenoviral (Ad) vector encoding for the murine IFN-beta gene (Ad.muIFN-beta) in mouse models of malignant mesothelioma. In contrast to multiple injections of recombinant protein, a single i.p. injection of Ad.muIFN-beta into animals with established tumors elicited remarkable antitumor activity leading to long-term survival in >90% of animals bearing either AB12 or AC29 i.p. mesotheliomas. A control adenovirus vector had minimal antitumor effect in vivo. Significant therapeutic effects were also seen in animals treated with large tumor burdens. Importantly, treatment of i.p. tumor also led to reduction of growth in tumors established at a distant site (flank). A number of experiments suggested that these effects were attributable to an acquired CD8(+) T-cell-mediated response including: (a) the induction of long-lasting antitumor immunity; (b) loss of efficacy of Ad.muIFN-beta in tumor-bearing, immune-deficient (SCID, SCID/beige) mice; (c) detection of high levels of specific antitumor cytolytic activity from unstimulated splenocytes harvested from Ad.muIFN-beta-treated animals that was abolished by CD8(+) T-cell depletion; and (d) abrogation of antitumor effects of Ad.muIFN-beta in tumor-bearing CD8(+) T-cell-depleted animals. These data show that intracavitary IFN-beta gene therapy using an adenoviral vector provides strong CD8(+) T-cell-mediated antitumor effects in murine models of mesothelioma and suggest that this may be a promising strategy for the treatment of localized tumors such as mesothelioma or ovarian cancer in humans.

Definitions of INTERLEUKIN on the Web:

• a cytokine secreted by immune system blood cells that regulates a range of immune functions. IL-2 is produced by activated CD4 cells and promotes the proliferation and activity of T-cells and natural killer cells.
   
• A substance used in biological therapy to help the immune system fight infection and cancer.
   
• A biological response modifier (substance that can improve the body's natural response to infection and disease) that helps the immune system fight infection and cancer. These substances are normally produced by the body. They are also made in the laboratory for use in treating cancer and other diseases.
   
• Any of several compounds produced by cells of the immune system that function in the regulation of the immune system
   
• cytokines that stimulate the growth and maturation of cells of the immune system.
   
• This is a generic term for cytokines produced by white blood cells when they are activated and in the process of killing or rejecting something such as an embryo, a kidney transplant or an infection. CD3-IL2 Receptor + cells are T cells in the process of rejection in the body. They should be below 5% of the total T cells in the immunophenotype testing.
   
• one of a large group of GLYCOPROTEINS that acts as CYTOKINES to communicate between LEUKOCYTES. The interleukins are secreted by and affect many different cells in the IMMUNE SYSTEM. See also INTERLEUKIN-1, INTERLEUKIN-2, INTERLEUKIN-4, INTERLEUKIN-10 and INTERLEUKIN-12.
   
• a whole family of proteins, some of which may be important in triggering inflammation in the joints. See also cytokine; lymphokine.
   
• Description: A protein produced naturally by our bodies to stimulate our immune systems. There are at least six kinds of interleukins. Source: Specialized encyclopedia and dictionaries
   
• Messenger molecule between the different cells of the immune system.
   
• A generic term for a group of protein factors produced by macrophages and T cells in response to stimulation by antigens or mitogens and affecting primary T cells.
   
• similar to interferon; a small protein produced by white blood cells to fight infections and some forms of cancer. There are many types of interleukins, numbered 1, 2, 3 ... up to 10 or more. Some interleukins have beneficial effects, others are harmful.
   
• in-ter-LUKE-in A class of immune system biochemicals. 792
   
• (IL) - a cytokine found in white blood cells that stimulates them to fight infection.
   
• (in-ter-LOO-kin): A substance used in biological therapy. Interleukins stimulate the growth and activities of certain kinds of white blood cells.
   
• a blood protein that helps fight infection and cancer
   
• any of several lymphokines that promote macrophages and killer T cells and B cells and other components of the immune system
   
• Interleukins are a group of cytokines that are expressed by white blood cells (leukocytes, hence the -leukin) as a means of communication (inter-). The function of the immune system depends in a large part on interleukins, and rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency.

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