TNF gene therapy

Radiation Combined with TNF Gene Therapy Induces Vascular Obliteration... 

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. 

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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. 

The number of clinical trials aimed at determining the safety and/or efficacy of cancer gene therapy continue to grow. The discussion herein is limited to trials that focus on treatments combined with radiation therapy. TNFerade is an adenovirus expressing the cytokine TNF-a under control of a radiation-induced promoter (Mundt et ah 2004). A phase 1 trial with TNFerade has been completed for metastatic solid tumors (Senzer et al. 2004). The treatment was well tolerated, with only... 

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