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 Bacterial cancer therapy is a concept more than 100 years old - yet, all things considered, it is still in early development. While the use of many passive therapeutics is hindered by the complexity of tumor biology, bacteria offer unique features that can overcome these limitations. Microbial metabolism, motility and sensitivity can lead to site-specific treatment, highly focused on the tumor and safe to other tissues. Activation of tumor-specific immunity is another important mechanism of such therapies. Several bacterial strains have been evaluated as cancer therapeutics so far, Salmonella Typhimurium being one of the most promising. S. Typhimurium and its derivatives have been used both as direct tumoricidal agents and as cancer vaccine vectors. VNP20009, an attenuated mutant of S. Typhimurium, shows significant native toxicity against murine tumors and was studied in a first-in-man phase I clinical trial for toxicity and anticancer activity. While proved to be safe in cancer patients, insufficient tumor colonization of VNP20009 was identified as a major limitation for further clinical development. Antibody-fragment-based targeting of cancer cells is one of the few approaches proposed to overcome this drawback.
The ability of various cytokines to hamper tumor growth or to induce anti-tumor im­mune response has resulted in their study as antitumor agents in gene therapy ap­proaches. In this review we will concentrate on the costimulation of antitumor immune re­sponses using modification of various cell types by cytokine genes. Several strategies have emerged such as (i) modification of tumor cells with cytokine genes ex vivo (whole tumor cell vaccines), (ii) ex vivo modification of other cell types for cytokine gene delivery, (iii) delivery of cytokine genes into tumor microenvironment in vivo, (iv) modification of dendritic cells with cytokine genes ex vivo. Originally single cytokine genes were used. Subsequently, multiple cytokine genes were applied simul­taneously, or in combination with other factors such as chemokines, membrane bound co-stimulatory molecules, or tumor associated antigens. In this review we dis­cuss these strategies and their use in cancer treatment as well as the promises and lim­itations of cytokine based cancer gene therapy. Clinical trials, including our own expe­rience, employing the above strategies are discussed.
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