Systemic administration of attenuated Salmonella typhimurium in combination with interleukin-21 for cancer therapy

Abstract

Attenuated () strain VNP20009 has been employed as a powerful anticancer agent due to its selective accumulation in tumors for targeted therapy. has been demonstrated to constitute a delivery tool carrying antiangiogenic or proapoptotic genes that treat cancer. The hydrodynamic tail vein (HTV) injection of naked plasmid DNA has been developed as an effective gene delivery strategy, which has been successfully used. The aim of this study was to develop a combination therapy of VNP20009 and HTV injection of interleukin-21 (IL-21) expression plasmid to evaluate the antitumor potential on an experimental melanoma model. Consistent with previous results, single VNP20009 treatment was demonstrated to possess effective activities to suppress tumor growth and prolong animal survival. Moreover, HTV injection of IL-21 plasmid promoted the antitumor activities of VNP20009. The mice that were administered combined therapy exhibited smaller tumor sizes and longer survival time compared with those administered VNP20009 or IL-21 treatment alone. IL-21 induced more infiltrating natural killer (NK) and T cells to the tumor area. These findings indicated that in combination with IL-21 promotes antitumor immune responses, suggesting a novel strategy in the treatment of cancer.

Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment

“…The smaller tumor size and longer survival time was observed in combination therapy than when administered alone. The anti-tumor immune response was attributed to the higher concentration of CD4+ and CD8+ lymphocytes and NK cells infiltration at the tumor site [ 97 ].…”

Targeted Cancer Therapy Using EngineeredSalmonella typhimurium

“…Because the growth of VNP20009 depends on the level of purine, they are more likely to colonize and proliferate in purine rich regions, such as tumor tissues. VNP20009 was examined in various murine cancer models, including melanoma, 9 breast cancer, 23 and colon cancer, 46 and in a canine model of spontaneous neoplasia. 69 …”

“…Attenuated S. typhimurium effectively inhibits tumor growth. 7 8 9 34 70 71 72 Native bacterial cytotoxicity is mediated by activation of the host immune system and by depriving cancer cells of nutrients. 39 Bacterial components (such as LPS, flagellin, and CpG) and signals/molecules released from damaged cancer cells activate the TLR and NLR signaling pathways, resulting in the production of proinflammatory cytokines (IL-1β, TNF-α, and IL-18), which mediate an antitumor immune response.…”

“…In the past 20 years, bacterial cancer therapy has again become a hot topic, and various kinds of bacteria have been the subject of preclinical and clinical research. Solid tumors have universal features, including abnormal blood vessels and hypoxic and necrotic regions; 2 3 these microenvironments are suited to colonization by, and facilitate proliferation of, obligatory or facultative anaerobic bacteria such as Streptococcus , 4 Clostridium , 5 Bifidobacterium , 6 Salmonella , 7 8 9 Escherichia coli , 10 11 12 and Listeria . 13 These bacteria specifically accumulate and proliferate inside tumor tissues, which can contain more than 1,000 times the number of bacteria found in reticuloendothelial organs like the liver or spleen.…”

Common gamma chain cytokines in combinatorial immune strategies against cancer

“…IL-21 shows its greatest potential when targeted directly to the tumor via a tumor-targeting vehicle. Tumor targeting molecules such as Salmonella typhimurium have been combined with IL-21 to promote suppression of tumor growth in B16F10 melanoma inoculated C57BL/6 mice [109]. …”