Squamous cell carcinoma (SCC) is the most common type of cancer affecting the oral cavity, the head, and neck, and is the fourth most common malignancy in male humans. Surgical tumor resection often adversely affects patient quality of life by removing essential organs, tissues, and nerves which affect breathing, eating, communicating, and social activity. Therefore, it is critical to find a less or non-invasive way of controlling tumor growth. Intratumoral injection of bleomycin via electroporation has proven very effective in treating highly malignant SCC tumors of the head and neck in a Phase II trial, resulting in 57% complete response. Unfortunately, this treatment does not prevent tumor recurrence, which is the primary factor to cause patient death. Furthermore, our study in mice also found that injection of bleomycin via intratumoral electroporation may decrease the size of the spleen, but that this side effect is able to be reversed by co-administration IL12 encoding DNA via electroporation. Additionally, our mouse study found that co-administration of IL12 also prevents tumor recurrence. Our preliminary study in two dogs also suggests that IL12 gene therapy may prevent tumor redevelopment when co-administered with bleomycin via electroporation. Based on these preliminary successes in mice and dogs, we are interested in testing whether IL12 gene therapy is truly effective at inhibiting tumor recurrence in the dogs treated with bleomycin;whether IL12 gene therapy can neutralize the toxicity of bleomycin on spleen cells and extend the survival time of dogs that receive intratumoral bleomycin treatment;and whether there are molecular markers which can predict tumor recurrence inhibition and survival time. The proposed studies are significant because tumors in dogs are heterogeneous, orthotopic, and naturally occurring, which may make them a better model for humans when compared to mice. Therefore results obtained from dogs will be valuable for translating this therapeutic into human clinics. Experience treating dogs will also be important for designing a successful human clinical study. Furthermore, dogs'large head and oral cavity allow us fully assess the invasiveness of this therapeutic approach. Our lab is well positioned for this study since we have an Animal Cancer Treatment Unit, which can recruit client-owned dogs;we have veterinary pathologists who can help diagnose tumor types and evaluate side effects;and we have experience using this therapeutic approach for treating dogs.
Tumor recurrence and metastasis after primary therapy to control and abate cancer growth are the major causes of death in cancer patients. The same is true for SCC-bearing patients for an otherwise very effective primary treatment-intratumoral bleomycin electroporation therapy. In order to inhibit post-treatment tumor recurrence, the current standard therapy, and bleomycin electroporation therapy have to be modified. IL12 is known to inhibit tumor angiogenesis, and change the tumor microenvironment from immunosuppressive to immunostimulatory. In this application, the applicant will test whether the use of IL12 gene therapy is able to inhibit tumor recurrence in dogs after primary bleomycin electroporation therapy. If the result is as expected, then IL12 and bleomycin combined therapy can greatly extend the survival-time of tumor bearing subjects and can be translated to humans. It is also reported that IL12 can neutralize the bleomycin-induced pulmonary fibrosis when systemically delivered. The applicant's preliminary mouse study indicates that IL12 neutralizes the toxic effect of bleomycin on spleen when bleomycin and IL12 were co-administered intratumorally. The applicant will examine whether this palliative effect is associated with extended survival.
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