Tumor regression induced by intratumoral injection of DNA coding for human interleukin 12 into melanoma metastases in gray horses

Abstract

Preclinical studies investigating new therapeutic principles against melanoma are presently being carried out in mouse models; however, these are not optimal. Here we describe a novel animal model using gray horses. These animals spontaneously develop metastatic melanoma that resembles human disease and is thus highly relevant for preclinical studies testing new immunotherapy protocols. We found that injection of plasmid DNA coding for the human cytokine interleukin 12 into established metastases induced significant regression in all 12 treated lesions in a total of 7 horses. Complete disappearance was observed in one treated lesion, with no recurrence after 6 months. No adverse events have been observed in any of the animals during and after treatment. These results demonstrate the effectiveness and safety of interleukin 12 encoding plasmid DNA therapy against established metastatic disease in a large animal model and serve as a basis for a clinical trial.

Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors

“…Several previous studies on different animal tumor models demonstrated, that more than one either intratumoral or intramuscular application of plasmid encoding IL-12 is necessary to achieve adequate therapeutic response in treated animals, even without systemically detectable IL-12 concentrations (Heinzerling et al, 2001; L.C. Heller et al, 2006;Lucas & R. Heller, 2003;Tevz et al, 2009).…”

Enhanced tumor immunogenicity through coupling cytokine expression with antigen presentation

“…25,26 Active immune responses against tumors have been successfully induced in many cases. However, the effects are often disappointing in clinical trials due to defects in antigen presentation and/or limited Genetically modifying the cytokine signal peptides X He et al antigen expression in human tumor cells.…”

Large animal models and gene therapy

“…78 A total of 12 metastatic lesions on seven horses were injected with plasmid DNA coding for human interleukin-12. 79 No side effects of the treatment were observed. Three intralesional treatments spaced 2 weeks apart resulted in tumor size reduction, ranging from complete resolution to a slight increase in size in one animal.…”

“…On average, the tumors decreased to 41% of their original size, whereas the untreated tumors increased slightly in size (107%) during the same time period. 79 Once the tumors had decreased in size and the treatment was discontinued, the tumors slowly grew larger but decreased again in response to an additional round of treatment with the plasmid DNA. 79 Histological evaluation of biopsies taken from the treated lesions revealed an influx of mainly CD4 but also CD8 lymphocytes around the tumors, which was never observed in the untreated control tumors.…”