Cancer interleukin-12 therapy

Toloza, E.M., Hunt, K., Swisher, S., McBride, W., Lau, R., Pang, S., Rhoades, K., Drake, T., Belldegrun, A., Glaspy, J. and Economou, J.S. (1996) In vivo cancer gene therapy with a recombinant interleukin-2 adenovirus vector. 

Y, Gauldie, J., Graham, F. L., Dancey, J., and Stewart, A. K. 2003. A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in high-risk localized prostate cancer. Cancer Gene Therapy, 10,755-763. 

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

Cytokines and biological response modifiers represent a broad class of therapeutic agents that modify the hosts response to cancer or cancer therapies. The enormous body information about their clinical uses and their side effects is beyond the scope of this essay that can only give illustrative examples. For an up-to-date information the reader can resort to reference [5]. As many as 33 different interleukins are known and the list continues to grow IL-2 used in the treatment of kidney cancer is one example. Interferon alpha is used for chronic myelogenous leukeia, hairy cell leukaemia and Kaposi s sarcoma. Interferons are also used in the treatment of chronic infections such as viral hepatitis. Tumor necrosis factor (alpha), G/GM/M-CSF, and several other cellular factors are used in treatment of various cancers. Many of these cytokines produce serious side effects that limit their use. 

Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin 2 therapy in patients with metastatic melanoma Long-term survival update. Cancer J Sci Am. 2000 6(suppl 1) SI 1-14. 

First clinical human gene therapy trials with polyplexes were performed using cancer vaccines based on autologous patient tumor cells. These were modified ex vivo with interleukin-2 pDNA. To obtain high level transfection rates of patient s primary tumor cells, Tf-PLL/pDNA polyplexes linked with inactivated endosomolytic adenovirus particles were applied [221]. Polymer-based in vivo human gene transfer studies were performed with PEGylated PLL polyplexes, delivering CFTR pDNA to the airway epithelium of cystic fibrosis patients [222],... 

Fewell JG, Matar MM, Rice JS, Brunhoeber E, Slobodkin G, Pence C, Worker M, Lewis DH, Anwer K (2009) Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally. J Gene Med 11 718-728... 

Also when the cytokine interleukin 2 (IL-2) was used for cancer treatment, serious adverse effects were noted resulting in the so-called vascular leak syndrome (VLS) [98, 99]. VLS is a life-threatening toxicity marked by vasopermeability with hypotension induced during high dose IL-2 treatment of cancer patients [100]. VLS is caused by endothelial activation and can be induced in lungs and liver of mice by IL2 administration [99]. The mechanism of IL-2-induced VLS is still poorly understood and at present there is no specific therapy for VLS. For the investigation of these... 

Bukowski, R.M., Natural history and therapy of metastatic renal cell carcinoma the role of interleukin-2. Cancer, 1997. 80(7) 1198-220. 

Waldmann TA. 2006. The biology of interleukin-2 and interleukin-15 Implications for cancer therapy and vaccine design. Nat Rev Immunol. 6 595-601. 

Li D, Jiang W, Bishop S, Ralston R, et al. 1999. Combination surgery and nonviral Interleukin-2 gene therapy for head and neck cancer. Clin Cancer Res. 5 1551-1556. 

Yamashita, Y., Shimada, M., Hasegawa, H., Minagawa, R., Rikimaru, T., Hamatsu, T. et al. (2001) Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res., 61, 1005-1012. 

Rakhmilevich, A.L., Janssen, K., Hao, Z., Sondel, P.M. and Yang, N.-S. (2000) Interleukin 12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T cell-independent mechanism. Cancer Gene Then, 7, 826-838. 

Tahara, H. and Lotze, M.T. (1995) Antitumor effects of interleukin-12 (IL-12) applications for the immunotherapy and gene therapy of cancer. Gene Then, 2, 96-106. 

Cell transfer therapy is a new approach to strengthening the innate ability of the immune system to fight against cancer (Figure 51.2). In this therapy, lymphocytes are isolated and cultured with interleukin-2 for 3 d to yield lymphokine-activated killer cells, which are then administered to patients along with interleukin-2. 

This is not to say that cardiotoxicity is not seen with biopharmaceuticals. Cardiomyopathy is now a well-recognized complication of trastuzumab and and has been reported with bevacizumab treatment, in particular in combination with other cytotoxic cancer therapies [20]. Myocarditis and pericarditis are a well-documented complications of vaccinia immunization [21], and could also complicate use of a pox-virus vector for other therapeutics. In 1995 Genetics Institute suspended phase 2 cancer trials of Interleukin-12 for serious tox-icities including cardiac arrhythmia. However, such toxicities are best detected by incorporation of biomarkers for myocardial damage such as troponin-T into preclinical and early clinical studies, and continual ECG monitoring for arrhythmia in preclinical and early clinical studies, not by in vitro explorations of electrophysiology. 

Autoimmune diseases have been reported to be more frequent in human subjects treated with several recombinant cytokines [38], For instance, increased titers or the new occurrence of autoantibodies have been observed in hepatitis C patients treated with the recombinant interferons-alpha (IFNa). Quite a few clinical case reports describe the development of organ-specific as well as systemic autoimmune diseases including systemic lupus erythematosus, insulin-dependent type I diabetes mellitus, autoimmune thrombocytopenia, autoimmune hemolytic anemia, myasthenia gravis, and autoimmune thyroiditis in patients under IFNa therapy. Although the mechanism involved is not fully elucidated, the available data support the pathogenic potential of IFNa in autoimmunity [31]. In contrast, autoimmune effects associated with IFNp therapy are thought to be of lesser concern based on the current clinical evidence [38], Thyroid autoimmunity in contrast to other autoimmune diseases is frequent in patients treated with recombinant interleukin-2 (rIL-2). Thus, among 281 previously euthyroid cancer patients treated with rIL-2, up to 41%... 

Recombinant human interleukin-4 (rhIL-4) is a monomeric protein with a molecular weight of 15,400 Da and pi of 9.2, with three intrachain disulfide bonds. It is a cytokine that has been investigated for cancer therapy. CZE of rhIL-4 mixtures prepared by in vitro degradation has been performed in uncoated capillaries with 50 m M 1,3-diaminopropane and phosphate buffers with pH ranging from 4.5 to 8.O.40 The resolution of degradation products by CZE appeared to be superior to HPLC. 

Walker LG, Wesnes KP, Heys SD, Walker MB, Lolley J, Eremin O. The cognitive effects of recombinant interleukin-2 (rIL-2) therapy a controlled clinical trial using computerised assessments. Eur J Cancer 1996 32A(13) 2275-83. 

Capuron L, Ravaud A, Dantzer R. Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy. J Clin Oncol 2000 18(10) 2143-51. 

Capuron L, Ravaud A, Miller AH, Dantzer R.Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or inter-feron-alfa cancer therapy. Brain Behav Immun 2004 18 205-13. 

Schomburg A, Kirchner H, Atzpodien J. Renal, metabolic, and hemodynamic side-effects of interleukin-2 and/or interferon alpha evidence of a risk/benefit advantage of subcutaneous therapy. J Cancer Res Clin Oncol 1993 119(12) 745-55. 

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