We currently have National Cancer Institute funding to study a gene therapy approach using an immune stimulatory cytokine, called IL12, in combination with radiation therapy and surgery for cats with vaccine induced sarcomas. 

This trial is being conducted in collaboration with colleagues at North Carolina State University (Drs. Thrall and Hauck) and Colorado State University (Dr. Susan Larue).  The gene therapy is triggered by using a heat inducible promoter to turn on the gene.  This promoter is referred to as the heat shock promoter.  
We have found in pre-clinical studies that the promoter is highly inducible.  In tissue cultured cells we observe over 30,000 fold induction of the gene, after heating to 42°C for one hour.

We have just started the cat trials and have treated four cats in a phase I trial.  The only thing that I can report so far is that we are able to see induction of the gene in the cat tumors and also we have not encountered any significant toxicity.  We are certainly hopeful that this new form of therapy will have important therapeutic benefit for cats with this disease.  Our long-term goal will be to translate this to human trials, however, the cat trials look promising.

Dr. Mark W. Dewhirst, DVM, PhD
Professor in Radiation Oncology
Adjunct Professor of Biomedical Engineering and Pathology
Duke University Medical Center

2001 ACVIM Forum
Denver, Colorado, May 23 - 26

Interleukin 12 (IL-12) has shown strong antitumoral effects in numerous pre-clinical studies and appears to act synergistically with radiation in murine tumors. The major impediment to its clinical use has been its systemic toxicity. While using intratumorally injected viral gene therapy vectors encoding IL-12 reduces systemic side effects substantially, elevated systemic transgene levels are still observed because adenovirus can reach the circulation and infect organs for which these viruses have high tropism (e.g. liver). Further restricting IL-12 expression in the tumor is therefore desirable in a combined radiation and adenovirus mediated cancer gene therapy regimen.

Hyperthermia-regulated gene therapy was tested in a non-immunogenic B16.F10 melanoma line that is syngeneic with C57BL/6 mice. For hyperthermic gene therapy an adenoviral vector coding for IL-12 under the control of the promoter of the human heat shock protein 70B (hsp70B) was used. One week after transplantation (at a 5-7 mm diameter), tumors were irradiated with 3 x 11 Gy (mo-we-fri). Adenovirus was injected at 3 x 10⁸ pfu/tumor 24 h before the last radiation fraction or 3 days afterwards. Hyperthermia was performed 24h later at 42.5° C. Growth delay to reaching three times initial tumor volume was chosen as the biological endpoint. IL-12 levels in tumor and serum were determined by using the enzyme-linked immunosorbant assay (ELISA).

Adenovirus mediated intratumoral expression of IL-12 under the control of a heat inducible promoter in combination with hyperthermia is almost as effective as that under the control of a constitutive cytomegaly virus (CMV) promoter while systemic transgene levels are substantially reduced with the heat inducible promoter. The combination of IL-12 gene therapy with hyperthermia yielded significant antitumor effect as did radiotherapy alone. However, the best response occured when radiation was added to the regimen. The improved effect was achieved without apparent systemic toxicity. When used as a single dose, applying IL-12 gene therapy after completion of radiotherapy appears to be beneficial.

Based on the encouraging results of these pre-clinical studies, we have initiated a phase I trial in cats with vaccine associated sarcomas that combines this thermal immunogene therapy approach with fractionated radiotherapy. This trial utilizes intra-tumorally administered adenoviral vectors containing the feline IL12 gene, under control of the heat shock promoter. Preliminary results of this trial will be presented.

Animal Study Shows That Heat-Sensitive Liposome Improves Chemotherapy Delivery to Tumors

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