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

IL12基因疗法增强博莱霉素抗口腔肿瘤的疗效

• 批准号: 8142751
• 负责人: SHULIN LI
• 金额: $ 31.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-14 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142751
• 关键词: Abate; Adverse effects; Affect; Aftercare; Animal Model; Animals; Bleomycin; Bone neoplasms; Breathing; Bystander Effect; Cancer Patient; Canis familiaris; Cause of Death; Cells; Cessation of life; Client; Clinic; Clinical Research; DNA; Diagnosis; Eating; Electroporation; Electroporation Therapy; Excision; Felis catus; Future; Genes; Goals; Growth; Head; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Immunosuppressive Agents; In complete remission; Injection of therapeutic agent; Interleukin-12; Intramuscular; Malignant Neoplasms; Malignant Squamous Cell; Methods; Modeling; Mouth Neoplasms; Mus; Neoplasm Metastasis; Neoplasms; Nerve Tissue; Northern Blotting; Operative Surgical Procedures; Oral; Oral cavity; Organ; Pathologist; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Positioning Attribute; Prevention; Primary Neoplasm; Pulmonary Fibrosis; Quality of life; Recruitment Activity; Recurrence; Recurrent tumor; Reporting; Research Design; Role; Spleen; Squamous cell carcinoma; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Translating; Treatment Efficacy; Tumor Angiogenesis; Tumor Volume; base; cDNA Arrays; cancer therapy; cancer type; design; experience; fascinate; gene therapy; human male; interest; malignant mouth neoplasm; molecular marker; non-viral gene delivery; novel; outcome forecast; palliative; plasmid DNA; prevent; response; social; success; tumor; tumor eradication; tumor growth

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.

描述(申请人提供)：鳞状细胞癌(SCC)是影响口腔、头和颈部的最常见的癌症类型，是男性第四种最常见的恶性肿瘤。手术切除肿瘤通常会切除影响呼吸、进食、沟通和社会活动的重要器官、组织和神经，从而对患者的生活质量产生不利影响。因此，寻找一种低侵袭性或非侵袭性的方法来控制肿瘤的生长是至关重要的。在II期试验中，通过电穿孔瘤内注射博莱霉素已被证明对治疗高度恶性的头颈部鳞状细胞癌非常有效，完全缓解率为57%。不幸的是，这种治疗不能防止肿瘤复发，而肿瘤复发是导致患者死亡的主要因素。此外，我们在小鼠身上的研究还发现，通过瘤内电穿孔注射博莱霉素可以减小脾的大小，但这种副作用可以通过电穿孔联合注射编码DNA的IL12来逆转。此外，我们的小鼠研究发现，联合应用IL12也可以防止肿瘤复发。我们在两只狗身上的初步研究也表明，当通过电穿孔与博莱霉素联合给药时，IL12基因治疗可以防止肿瘤再发展。基于这些在小鼠和狗身上的初步成功，我们有兴趣测试IL12基因治疗是否真的能有效地抑制博莱霉素治疗的狗的肿瘤复发；IL12基因治疗是否可以中和博莱霉素对脾细胞的毒性并延长接受博莱霉素治疗的狗的生存时间；以及是否有分子标志物可以预测肿瘤复发抑制和生存时间。这项拟议的研究意义重大，因为狗的肿瘤是异质的、原位的和自然发生的，这可能使它们成为人类比小鼠更好的模型。因此，从狗身上获得的结果对于将这种疗法转化为人类临床将是有价值的。治疗狗的经验对于设计一项成功的人类临床研究也是重要的。此外，狗的大头部和口腔使我们能够充分评估这种治疗方法的侵入性。我们的实验室为这项研究做好了准备，因为我们有动物癌症治疗单位，可以招募客户拥有的狗；我们有兽医病理学家，他们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。