Treatment of murine hepatocellular carcinoma using genetically modified cells to express interleukin‐12

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Abstract
Background and Aim: The majority of patients cannot benefit from the conventional curative treatments that are currently used for hepatocellular carcinoma (HCC), which remains a world health problem. Interleukin (IL)‐12 is one of the most potent anti‐tumor cytokines. The aim of the present study was to examine the anti‐tumor effect and toxicity of intrahepatic delivery of IL‐12 using an ex vivo gene therapy approach in a murine model of HCC. Methods: Syngenic fibroblasts or MM45T‐Li HCC tumor cells were genetically modified in vitro to express IL‐12 using a polycistronic TFG murine IL‐12 retroviral vector (TFGmIL‐12) coding for both p35 and p40 murine IL‐12 subunits. Hepatocellular carcinoma was generated using direct intrahepatic inoculation of the tumor cell line into the left liver lobe of BALB/c mice. Results: Direct liver expression of IL‐12 by the injected genetically modified tumor cells induced a marked inhibition of tumor growth. This effect was associated with an early infiltration of macrophages, and lymphocytes forming numerous intralobular foci. There was no significant liver toxicity, as shown by normal biochemical liver tests. At a later time, the intralobular foci were rare and consisted mainly of CD4+ T cells, while CD8+ T cells were present in the lobule. Intrahepatic expression of IL‐12 did not modify circulating or splenic B lymphocytes or natural killer (NK) cells. The inhibition of tumor growth was maintained in nude mice even when depleted in NK cells. Importantly, in a second model, treatment of established day 7 liver tumors in BALB/c mice using direct intra‐tumor injection of syngenic fibroblasts that were genetically modified to express IL‐12 significantly reduced tumor size. Conclusion: In conclusion, these data provide evidence that experimental HCC can be efficiently and safely treated using ex vivo IL‐12 gene therapy, which seems promising for future clinical studies.