Tumor-Specific Targeting by Means of Attenuated Salmonella

It has been reported earlier that intravenously applied bacteria not only accumulate in tumors but can also sporadically lead to tumor-regression. The preferred accumulation of bacteria in tumors can be explained by a variety of mechanisms, such as nutrients, especially purine, provided by rapidly growing tumor cells and necrotic cells, adaptation of salmonella to growth in hypoxic areas, lack of bactericidal activity of macrophages and neutrophile granulocytes due to lack of oxygen, suppression of the immune system in tumor regions, lack of granulocytic infiltrates due to secretion of cytokines such as TGF-ß, absence of circulating antibodies as well as complement-factors due to irregular vasculature and positive pressure within tumors. The oncolytic activity can be explained by means, such as asparaginase production by bacteria that depletes tumors from essential amino acids, secretion of local toxins, inhibition of angiogenesis via production of TNF-a, alteration of anti-tumor T cells due to nonspecific inflammatory responses. Furthermore, systemic administration of attenuated Salmonella typhimurium has already been demonstrated to result in no significant side effects in humans. Consequently, we decided to make use of such bacteria and to improve their oncolytic activity by utilizing their inherent capacity to infect host cells. In this study, we will make use of several cytokines that have already been shown extensively to allow for tumor-rejection. These cytokines, carried by attenuated Salmonella typhimurium, will then be tested for their potential to inhibit the growth of primary tumors as well as the dissemination of pulmonary metastases in various therapeutic models of multi-drug resistant clones of murine carcinoma cell lines. In summary, this therapeutic approach is anticipated to significantly ameliorate cancer-therapy by improving delivery of therapeutic proteins to tumors using attenuated salmonella.

In this study, we made use of several cytokines that have already been shown extensively to allow for tumor- rejection. These cytokines, carried by attenuated Salmonella typhimurium, demonstrated potential to inhibit the growth of primary tumors as well as the dissemination of pulmonary metastases in various therapeutic models of multi-drug resistant clones of murine carcinoma cell lines. In summary, this therapeutic approach is anticipated to significantly ameliorate cancer-therapy by improving delivery of therapeutic proteins to tumors using attenuated salmonella.