Tumor necrosis factor gene therapy

Standiford TJ, Wilkowski JM, Sisson TH, Hattori N, Mehrad B, Bucknell KA, et al. Intrapulmonary tumor necrosis factor gene therapy increases bacterial clearance and survival in murine gram-negative pneumonia. Hum Gene Ther 1999 10(6) 899-909. 

Mugnier, B., Balandraud, N., Darque, A., Roudier, C., Roudier, J., and Reviron, D. (2003) Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis and Rheumatism. 48, 1849-1852. 

Ad.TNF gene therapy is presently in clinical trials in patients receiving radiotherapy. An open-label, phase I, dose-escalation study of tumor necrosis factor-alpha (TNFerade) gene transfer with radiation therapy for locally advanced, recurrent, or metastatic solid tumors is currently accruing patients and has several endpoints (82), including toxicity and tolerable dose. Pharmacokinetics will be evaluated and biological correlates will determine the histologic response to therapy. 

Mauceri HJ, Hanna NN, Wayne JD, et al. Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 1996 56 4311-4314. 

A replication-deficient adenovirus has been used to deliver a gene construct, which contains within its promoter region a radiation-responsive element. Upon irradiation with conventional doses of X rays, this construct initiates transcription of the gene coding for the toxic cytokine, tumor necrosis factor-a (35). The above is an exquisite example of how emerging delivery and gene therapies are fast blurring the distinction between an active and an excipient (Fig. 3D). 

Qin, L., Ding, Y., Pahud, D.R., Chang, E., Imperiale, M.J. and Bromberg, J.S. (1997) Promoter attenuation in gene therapy interferon-gamma and tumor necrosis factor-alpha inhibit transgene expression. Hum. Gene Then, 8, 2019-2029. 

Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-kapptiB in hippocampal synaptic plasticity. Synapse 35 151-159 Baltimore D (1988) Gene therapy intraceUular immunization. Nature 335 395-396 Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J et al (1995) Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 92 9328-9332... 

Ongaro A, De Mattei M, Pellati A, Caruso A, Ferretti S, Masieri FF et al (2008) Can tumor necrosis factor receptor II gene 676T>G polymorphism predict the response grading to anti-TNFalpha therapy in rheumatoid arthritis Rheumatol Int 28 901-908... 

Plant D, Prajapati R, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD et al (2012) Replication of association of the PTPRC gene with response to anti-tumor necrosis factor therapy in a large UK cohort. Arthritis Rheum 64 665-670... 

To enhance tumor toxicity by using the cells own defense system, expression of various cytokines and other immunomodulatory proteins have been investigated as potential strategies for radiosensitization when expressed from various vectors. As with other combined modalities, the combinations of cytokine gene therapy with radiation or chemotherapy have shown some promise in clinical settings. The most advanced studies are those based on tumor necrosis factor-a (TNF-a) in combination with radiation (Kufe and Weichsel-BAUM 2003). TNF-a has potent antitumor and antiangiogenesis activities that synergize with radiation therapy. TNFerade was developed as an ADV that expressed TNF-a under control of a radiation-inducible promoter that limits toxicities to the irradiated area, which is not the case with the direct injection of TNF-a into the tumor. 

Klooster, A. R. and Bernier, S. M. 2005. Tumor necrosis factor alpha and epidermal growth factor act addi-tively to inhibit matrix gene expression by chondrocyte. Arthritis Research Therapy, 7, R127-R138. 

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