Combination gene therapy for metastatic colon cancer

转移性结肠癌的联合基因治疗

• 批准号: 6435182
• 负责人: Shu-Hsia Chen
• 金额: $ 30.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6435182
• 关键词: Adenoviridae; CD40 molecule; SCID mouse; T cell receptor; anergy; antigen presenting cell; antineoplastics; apoptosis; cell cell interaction; cell proliferation; colon neoplasms; combination cancer therapy; cytotoxic T lymphocyte; flow cytometry; gene therapy; genetically modified animals; helper T lymphocyte; hemagglutinin; immune tolerance /unresponsiveness; interleukin 12; leukocyte activation /transformation; metastasis; monoclonal antibody; neoplasm /cancer immunology; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): In the U.S., metastatic colon carcinoma is second only to lung cancer as the cause of death from malignancy in the United States, accounting for 60,000 fatalities a year. 80 percent of the patients who died of colon cancer have metastases in the liver, and half of them have only liver metastases at the time of death. Current treatments include surgery and chemotherapy, with a mean survival time of only 37 months. Using an orthotopic murine model for pre-established hepatic colon cancer, we have shown that intratumoral injection of an adenoviral vector expressing murine interleukin-12 (Adv.mIL-12) led to tumor regression and prolonged survival of treated mice. However, the anti-tumor immunity induced by this type of gene therapy was mediated primarily by natural killer (NK) cell. In order to also induce a tumor specific T cell response as well, we co-administered an agonistic monoclonal antibody against murine 4-1BB, a co-stimulatory molecule on activated T cells, to induce CD8+ T cell activation and proliferation. The combination treatment resulted in the induction of a strong anti-tumoral immunity and 80 percent long-term survival in the tumor-bearing animals (5x5 m2), even with an eighteen-fold reduction of the Adv.RSV-mIL-12 dose. However, the combination treatment can only induce an NK and CD8+ T cells mediated anti-tumor responses and is less effective for large tumors (lOx10 mm2). In order to achieve persistent anti-tumor immunity and improve therapeutic effect when treating large tumors, the activation of CD4+ T helper cells will be incorporated into the combination therapy via agonistic antibodies against the co-stimulatory molecule OX40, an activation molecule on activated CD4 T helper cells, or CD40, an activation molecule on activated antigen presenting cells (APC). Three specific aims will be pursued: 1) To determine whether intra-tumoral IL-12 gene delivery in conjunction with agonistic antibodies against 4-1BB plus OX40 and/or CD40 can achieve better therapeutic effect for large tumors and generate persistent anti-tumor immune responses to prevent residual and metastatic tumors. 2) To examine the role of CD4 T cells in the accentuated development of tumor specific CD8 memory T cells in combination treated animals. 3) To investigate whether the CD4O and OX 40 activated immune cells can overcome the immune tolerance in mice with a large tumor burden. Successful completion of these studies will result in a better understanding of the interaction of APC, CD4, and CD8 cells in the establishment of anti-tumor memory CD8 T cells and immune suppression/tolerance mediated by a large tumor burden. These therapeutic strategies will be utilized as the scientific foundation for active immune modulation of patients with metastatic colorectal cancer.

描述（由申请人提供）：在美国，转移性结肠癌是 在美国，肺癌是恶性肿瘤死亡的第二大原因， 每年有6万人死亡。80%的患者 死于结肠癌的人有肝脏转移，其中一半只有 死亡时有肝转移目前的治疗方法包括手术和 化疗，平均生存时间只有37个月。使用一个正交的 预先建立的肝结肠癌小鼠模型，我们已经表明， 肿瘤内注射表达鼠白细胞介素-12的腺病毒载体 （Adv.mIL-12）导致肿瘤消退并延长治疗小鼠的存活。 然而，这种类型的基因治疗诱导的抗肿瘤免疫是 主要由自然杀伤（NK）细胞介导。为了诱发肿瘤 特异性T细胞应答，我们共同给予激动性单克隆抗体， 抗鼠4-1BB抗体，一种活化T细胞上的共刺激分子， 以诱导CD 8 + T细胞活化和增殖。联合治疗 导致诱导强烈的抗肿瘤免疫， 在荷瘤动物（5x 5 m2）中的长期存活率，即使在 将Adv.RSV-mIL-12剂量降低18倍。然而， 治疗只能诱导NK和CD 8 + T细胞介导的抗肿瘤应答 并且对于大肿瘤（10 × 10 mm 2）不太有效。为了实现 持续的抗肿瘤免疫力，提高治疗效果， 在大肿瘤中，CD 4 + T辅助细胞的激活将被纳入 通过针对共刺激因子的激动性抗体的联合治疗 分子OX 40，活化的CD 4 T辅助细胞上的活化分子，或CD 40， 活化抗原呈递细胞（APC）上的活化分子。三 本研究的具体目的是：1）确定肿瘤内IL-12基因是否与肿瘤细胞的增殖和分化有关， 与针对4-1BB加OX 40的激动性抗体联合递送 和/或CD 40可以对大肿瘤达到更好的治疗效果， 持续的抗肿瘤免疫应答，以防止残留和转移 肿瘤的2)为了研究CD 4 T细胞在恶性淋巴瘤加重发展中的作用， 肿瘤特异性CD 8记忆T细胞。3)到 研究CD 40和OX 40激活的免疫细胞是否可以克服 在具有大肿瘤负荷的小鼠中的免疫耐受性。成功完成 这些研究将导致更好地理解APC的相互作用， CD 4和CD 8细胞在建立抗肿瘤记忆性CD 8 T细胞和 免疫抑制/耐受由大的肿瘤负荷介导。这些 治疗策略将被用作积极的科学基础， 转移性结直肠癌患者的免疫调节。