Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

“…27 The antitumor effects of Ad/IL-12 have been demonstrated in several orthotopic HCC animal models, including mouse, rat and woodchuck. 28–30 However, Ad/IL-12 alone failed in clinical trials of patients with hepatic malignancy. 31 One of the challenges in treating established hepatic tumor with immunotherapy is to induce anti-tumor immune responses within the tolerogenic microenvironment of the liver and in the hepatic tumor.…”

Prolonged and inducible transgene expression in the liver using gutless adenovirus: A potential therapy for liver cancer

“…IL-12 is a potent cytokine with robust antitumor effects. [27][28][29]32 The systemic administration of the recombinant protein to treat cancer has found the limitation of toxicity due to the ability of IL-12 to strongly induce interferon gamma production. 33,34 Adenovirus-mediated gene transfer of IL-12 to the tumor or peritumoral tissue causes a gradient of IL-12 concentration with higher values at the site of the neoplasm and lower systemic levels, resulting in increasing antitumor efficacy and wider therapeutic window.…”

“…25,26 Therapy of established tumors with first generation adenoviruses encoding interleukin-12 (IL-12) has been very effective in different animal models of transplanted tumors. [27][28][29] However, although in our phase I/II study, the intratumor administration of firstgeneration adenovirus encoding human IL-12 (hIL-12) has been well tolerated, the antitumor effects were quite weak. 30 This lack of efficacy likely depends on short duration of transgene expression and on the fact that the tumor tissue is not easily infected with adenoviral vectors.…”

Upregulation of natural killer cells functions underlies the efficacy of intratumorally injected dendritic cells engineered to produce interleukin-12

“…In immunotherapy, endogenous NK cells have been found necessary when using IL-12 as a protein [32] or as transfected gene, but it should be noted that their involvement is found in some models but not in others [17,21,46,47]. A role for those lymphoid NK subpopulations has also been found in other immunotherapeutic approaches such as in the transfection of CD80 into melanoma cells [30] or in the treatment with immunostimulating anti-4-1BB mAb [31].…”