IL12 Gene Therapy For Enhancing Therapeutic Efficacy of Bleomycin Against Oral Tu

描述（由申请人提供）：鳞状细胞癌（SCC）是影响口腔、头部和颈部的最常见癌症类型，是男性中第四常见的恶性肿瘤。外科肿瘤切除术通常通过切除影响呼吸、进食、交流和社会活动的重要器官、组织和神经而对患者的生活质量产生不利影响。因此，找到一种微创或非侵入性的方法来控制肿瘤生长至关重要。通过电穿孔瘤内注射博来霉素在II期试验中已被证明在治疗头颈部高度恶性SCC肿瘤方面非常有效，导致57%的完全缓解。不幸的是，这种治疗不能防止肿瘤复发，这是导致患者死亡的主要因素。此外，我们在小鼠中的研究还发现，通过肿瘤内电穿孔注射博来霉素可减小脾脏的大小，但这种副作用能够通过经由电穿孔共同施用编码IL 12的DNA来逆转。此外，我们的小鼠研究发现，IL 12的共同施用也防止肿瘤复发。我们在两只狗中的初步研究还表明，当通过电穿孔与博来霉素共同给药时，IL 12基因治疗可以防止肿瘤再发展。基于这些在小鼠和狗中的初步成功，我们感兴趣的是测试IL 12基因治疗是否真的有效抑制用博来霉素治疗的狗的肿瘤复发; IL 12基因治疗是否可以中和博来霉素对脾细胞的毒性并延长接受瘤内博来霉素治疗的狗的存活时间;是否存在预测肿瘤复发抑制和生存期的分子标志物。这项研究意义重大，因为狗的肿瘤是异质的、原位的和自然发生的，这可能使它们成为比小鼠更好的人类模型。因此，从狗身上获得的结果对于将这种治疗方法转化为人类临床将是有价值的。治疗犬的经验对于设计成功的人类临床研究也很重要。此外，狗的大头和口腔使我们能够充分评估这种治疗方法的侵入性。我们的实验室非常适合这项研究，因为我们有一个动物癌症治疗单位，可以招募客户拥有的狗;我们有兽医病理学家可以帮助诊断肿瘤类型和评估副作用;我们有使用这种治疗方法治疗狗的经验。

DESCRIPTION (provided by applicant): 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.