Combination gene therapy for metastatic colon cancer

转移性结肠癌的联合基因治疗

• 批准号: 7104613
• 负责人: Shu-Hsia Chen
• 金额: $ 29.57万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104613
• 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): The current treatment options for metastatic colon carcinoma are limited. Our preclinical research indicates that immune-modulatory gene therapy may be effective for the treatment of advanced metastatic colorectal cancer. Using an orthotopic murine model for pre-established hepatic colon carcinoma, we have shown that intratumoral injection of an adenoviral vector expressing murine interleukin-12 (Adv/mIL-12) and 4-1BB, a co-stimulatory molecule normally found on activated dendritic and T cells, can induce dendritic cell and CD8+ T cell activation and proliferation. This leads to tumor regression and prolonged survival of treated mice. However, this therapeutic effect is significantly compromised by large tumor burdens (>8x8-10x10mm2). Significant accumulation of myeloid suppressor cells (MSC) and T regulatory cells (Treg) were found in animals bearing large tumors. The lack of proper antigen presentation and Treg mediated immune suppression are two of the main means by which tumor cells evade the immune system and present the major obstacles for cancer immune therapy. We found that CD 40 engagement greatly improved the long-term survival rate of mice bearing large tumors when used in conjunction with IL-12 + anti-4-lBB combination therapy. Furthermore, agonistic anti-CD40 antibody prevented MSC-mediated Treg induction. We hypothesize that CD40 activation by agonistic antibody or Ig-CD40 ligand fusion protein can enhance anti-tumor responses through multiple mechanisms: 1) CD40 ligation can prevent Treg induction through CD40 signaling on MSC; 2) CD40 activation can induce the differentiation of MSC into dendritic cells and downregulate the inhibitory receptors, PIR-B (paired Ig-like receptor B) and gp49b, which are highly expressed on MSC and immature DCs. Three specific aims will be pursued in order to understand the mechanisms underlying the CD40 mediated regulation of MSC function and reversion of immune suppression in the large tumor setting: 1) Study the mechanisms underlying the prevention of MSC-induced Treg development by anti-CD40 ligation; 2) Investigate the negative receptor signals as the potential mechanism behind the ineffective anti-tumor response to synergistic IL-12 and 4-1BB activation in mice with large tumor burdens; 3) Determine the therapeutic effect of blocking negative inhibitory receptors and reversing immune suppression by co-stimulatory molecules on the persistence of an effective anti-tumor response following immune activation in the large tumor bearing host. The completion of these studies will not only provide a new insight into the mechanisms of tumor mediated suppression and tolerance, but also facilitate effective clinical translation of our immune enhancing therapy.

描述（由申请人提供）：目前转移性结肠癌的治疗选择有限。我们的临床前研究表明免疫调节基因疗法可能对晚期转移性结直肠癌的治疗有效。利用原位小鼠肝结肠癌模型，我们发现瘤内注射表达小鼠白细胞介素-12 （Adv/mIL-12）和4-1BB的腺病毒载体可以诱导树突状细胞和CD8+ T细胞的活化和增殖。4-1BB是一种通常存在于活化的树突状细胞和T细胞上的共刺激分子。这导致肿瘤消退和延长治疗小鼠的生存期。然而，这种治疗效果明显受到大肿瘤负荷（bb0 8x8-10x10mm2）的影响。骨髓抑制细胞（MSC）和T调节细胞（Treg）在大肿瘤动物中显著积累。缺乏适当的抗原呈递和Treg介导的免疫抑制是肿瘤细胞逃避免疫系统的两种主要手段，也是癌症免疫治疗的主要障碍。我们发现，当与IL-12 +抗-4- lbb联合治疗时，cd40结合可大大提高大肿瘤小鼠的长期生存率。此外，激动性抗cd40抗体阻止msc介导的Treg诱导。我们推测，通过激动抗体或igg -CD40配体融合蛋白激活CD40可通过多种机制增强抗肿瘤反应：1)CD40连接可通过MSC上的CD40信号传导阻止Treg诱导；2)激活CD40可诱导间充质干细胞向树突状细胞分化，下调抑制受体PIR-B（配对igg样受体B）和gp49b在间充质干细胞和未成熟dc上的高表达。为了了解CD40介导的间充质干细胞功能调节和大肿瘤免疫抑制逆转的机制，将追求三个具体目标：1)研究通过抗CD40连接预防间充质干细胞诱导的Treg发育的机制；2)探讨负受体信号作为大肿瘤负荷小鼠对IL-12和4-1BB协同激活无效抗肿瘤反应的潜在机制；3)确定共刺激分子阻断负抑制受体和逆转免疫抑制对大荷瘤宿主免疫激活后有效抗肿瘤反应持续的治疗效果。这些研究的完成不仅将为肿瘤介导的抑制和耐受机制提供新的见解，而且还将促进我们的免疫增强治疗的有效临床转化。