Attenuated bacteria as effectors in cancer immunotherapy

Despite the great strides made in understanding the basic biology of cancer and the multiple approaches to cancer therapy that have been utilized, cancer remains a major cause of death worldwide. The two properties that define the most successful tumors are low antigenicity, enabling cancer cells to escape immune system recognition, and high tumorigenicity, allowing the cells to proliferate aggressively and metastasize to other tissues. The development of novel anticancer therapies is aimed at enhancing the antigenicity of tumors and/or increasing the functional efficiency of various effector immune system cells. The use of obligate/facultative anaerobic bacteria, which preferentially replicate within tumor tissue, as an oncolytic agent is one of the innovative approaches to cancer therapy. Over the past several years, we have studied the properties of attenuated strains of Salmonella typhimurium, a facultative anaerobe, genetically engineered to express murine cytokines. Previously, we demonstrated that cytokine-expressing strains have the capacity to modulate immunity to infection. Given the preferential tumor-homing properties of attenuated Salmonella bacteria, the potential capacity of a cytokine-encoding Salmonella strain to retard the growth of experimental melanomas was investigated. Mice pre-implanted with melanoma cells were treated with an attenuated strain of S. typhimurium or with one of its derivatives expressing IL-2. Our data demonstrate that IL-2-encoding Salmonella organisms were superior in suppressing tumor growth as compared to the parental noncytokine-expressing strain. This supports the notion of using cytokine-expressing attenuated Salmonella organisms in cancer therapy.