The objective of the present study was to investigate the effects of mesenchymal stem cells (MSCs) genetically modified by lentivirus-mediated mouse interleukin-12 (Lenti-mIL-12) in treating malignant ascites in mice. The in vitro chemotactic effect of Lenti-mIL-12-MSC culture supernatant on dendritic cells was investigated using a chemotaxis chamber. Liver cancer H22 and MethA ascites models were constructed. Mice were divided evenly into four groups: Normal saline, MSC, Null and Lenti-mIL-12-MSC. The survival rate, ascites volume and red blood cell number were measured for these groups. The toxicity and side effects of Lenti-mIL-12-MSCs were investigated using visual and microscopy inspections. The results indicated that mIL-12 had a strong chemotactic effect on dendritic cells. mIL-12 was highly expressed in ascites of Lenti-mIL-12-MSC-treated mice. Lenti-mIL-12-MSCs reduced the volume of ascites and the number of red blood cells in ascites and thus increased the survival rate and prolonged the survival duration of the mice. Furthermore, Lenti-mIL-12-MSCs showed no toxicity and side effects on the mice with malignant ascites. In conclusion, the results demonstrated that Lenti-mIL-12-MSCs inhibited the growth of ascites and promoted the survival of tumor-bearing mice, suggesting that Lenti-mIL-12-MSCs exerts a therapeutic effect on malignant ascites by stimulating the immune responses of the mice.

10 Apr 2002·Human Gene TherapyQ2 · MEDICINE

Intratumoral Delivery of Adenovirus-Mediated Interleukin-12 Gene in Mice with Metastatic Cancer in the Liver

Q2 · MEDICINE

Article

Author: Chen, Shu-Hsia ; Mandeli, John P. ; Thung, Swan N. ; Zhang, David Y. ; Woo, Savio L.C. ; Sung, Max W. ; Huang, Tian-Gui

Clinical trials of recombinant human interleukin-12 (rhIL-12) delivered by intravenous administration have shown dose-limiting toxicities with limited tumor responses at the doses tested. We have previously reported that intratumoral injection of an adenovirus vector expressing murine interleukin-12 (Adv.RSV-mIL-12) was effective in inducing antitumor immune responses, tumor regression, and long-term survival in mice with established metastatic cancer in the liver. We now report additional studies in the same murine tumor model to assess the safety of intratumoral Adv.RSV-mIL-12 injection. At vector doses that were previously shown to be therapeutically effective, no inflammation in the liver or lungs, and no significant elevations in serum creatinine and aminotransferases were seen after vector injection. Serum elevations of IL-12 and interferon-gamma (IFN-gamma) were 17- and 19-fold lower than peak levels after intravenous recombinant IL-12 at the maximal tolerated dose in clinical trials. No elevations in serum proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha) were noted up to 2 weeks after vector injection. No systemic dissemination of the vector was detected on polymerase chain reaction (PCR) assays at therapeutically effective vector doses. At higher supratherapeutic vector doses of Adv.RSV-mIL-12, however, inflammation in the liver and lungs with elevation in serum aminotransferases were seen, but not in controls injected with the equivalent particle number of an empty adenoviral vector. These results support the cautious testing in patients with hepatic metastases of adenovirus mediated IL-12 gene delivery by intratumoral injection.

01 Jan 2001·Journal of ImmunotherapyQ4 · MEDICINE

Low-Dose Vaccinia Virus-Mediated Cytokine Gene Therapy of Glioma

Q4 · MEDICINE

Article

Author: Gridley, Daila S. ; Timiryasova, Tatyana M. ; Kajioka, Eric H. ; Fodor, Istvan ; Andres, Melba L. ; Haghighat, Peyman ; Dutta-Roy, Radha ; Chen, Bing

Recombinant viruses can produce cytokines in tumors mobilizing an immune response to tumor cells. In this study, the authors investigated gene expression, in vivo antitumor efficacy, and safety of attenuated recombinant vaccinia virus (rVV) carrying murine cytokine genes interleukin (IL)-2 (rVV-mIL-2), IL-12 (rVV-mIL-12), and both IL-2 and IL-12 (rVV-2-12) in an athymic nude mice model. Significant tumor inhibition (p < 0.05) was observed in a preestablished subcutaneously implanted C6 glioma model using rVVs at doses ranging from 10(2) to 10(7) plaque forming units (PFU). An antitumor effect did not depend on the dose of the rVV-mIL-2 and rVV-mIL-12 viruses. All constructed rVVs induced a high level of cytokine expression in vitro and in vivo. Most groups injected with high doses of recombinant viruses encoding cytokine genes (10(5) to 10(7) PFU) showed signs of cytokine toxicity, whereas in the low-dose treatment groups (10(2) to 10(3) PFU) toxicity was greatly reduced. The antitumor activity of rVV-mIL-12 was associated with increases in both the percentage and number of natural killer T cells in the spleen. Local detection of interferon-y and tumor necrosis factor-alpha was also correlated with tumor growth arrest induced by the treatment. High-dose VV control vector per se induced tumor inhibition by activating Mac-1+ cells in blood, but the antitumor effect was less pronounced compared with rVV-carrying cytokine genes (p < 0.05). These results suggest that attenuated recombinant strains of VV at low doses may potentially be efficient vectors for cancer immunotherapy.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Synthekine, Inc.Startup	17 Apr 2023

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