Oral Immune Modulatory Adjuvants for Treatment of Colorectal Carcinoma

口服免疫调节佐剂治疗结直肠癌

• 批准号: 8268985
• 负责人: NEJAT K EGILMEZ
• 金额: $ 19.92万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268985
• 关键词: Adenocarcinoma; Adenomatous Polyps; Adjuvant; Adoptive Transfer; Adverse effects; Aftercare; Anti-Inflammatory Agents; Antibodies; Cancer Etiology; Carcinoma; Cessation of life; Chronic; Clinical Trials; Colon; Colorectal Cancer; Data; Dendritic Cells; Development; Disease; Drug Formulations; Effector Cell; Equilibrium; Future; Generations; Homeostasis; Immune; In Situ; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-9; Intestinal Neoplasms; Intestinal Polyposis; Intestines; Laboratories; Lamina Propria; Large Intestine Carcinoma; Lead; Link; Mediator of activation protein; Mesentery; Modality; Modeling; Mus; Oral; Oral Administration; Particulate; Pathway interactions; Pharmaceutical Preparations; Polyps; Production; Regulatory T-Lymphocyte; Role; Source; Symptoms; T-Lymphocyte; Testing; Therapeutic; Tretinoin; Tumor Suppression; Work; adenoma; base; carcinogenesis; controlled release; cytokine; design; high risk; inhibitor/antagonist; lymph nodes; mast cell; mouse model; nanoparticle; nanoparticulate; novel; novel therapeutics; particle; small molecule; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Adoptive transfer of T-regulatory cells (Treg) can induce tumor regression in murine models of intestinal polyposis and carcinoma revealing an important role for Treg in controlling tumor-promoting inflammation in the gut. Separately, studies in PI's laboratory demonstrated that oral administration of sustained-release TGF¿ and all-trans retinoic acid (ATRA) formulations, two essential mediators of mucosal Treg generation in the gastro-intestinal (GI) tract, can result in effective suppression of disease symptoms in a murine model of inflammatory bowel disease (IBD). These findings gave rise to the notion that oral immune-modulatory adjuvants designed to restore immune homeostasis in the GI tract may also be useful in the treatment of inflammation-associated colorectal carcinoma (CRC). In initial studies short-term oral TGF¿/ATRA particle therapy resulted in a dramatic regression of established polyps in the APCMin/+ mice providing strong proof-of- concept. Based on these data, two different therapeutic strategies targeting: a) in situ Treg generation and b) direct suppression of tumor-promoting inflammatory effectors, are evaluated in murine models of spontaneous intestinal polyposis and carcinogenesis. More specifically, in Aim 1 the ability of oral sustained-release TGF¿/ATRA nanoparticles to achieve long-term eradication of established spontaneous adenomas and adenocarcinomas is tested in two different embodiments of the APCMin/+ mouse model. In Aim 2 oral nanoadjuvants targeting the pro-tumorigenic inflammatory T-cell/mast cell axis, i.e. controlled-release formulations of anti-IL-9 antibody and Masitinib, are evaluated in the same models. If successful, these studies can lead to a new therapeutic paradigm in the management of CRC.

描述（由申请人提供）：调节性T细胞（Treg）的过继转移可以在肠息肉病和癌症的小鼠模型中诱导肿瘤消退，揭示Treg在控制肠道内促肿瘤炎症方面的重要作用。另外，PI 实验室的研究表明，口服缓释 TGF 和全反式视黄酸 (ATRA) 制剂（胃肠道 (GI) 中粘膜 Treg 生成的两种重要介质）可以有效抑制炎症性肠病 (IBD) 小鼠模型中的疾病症状。这些发现引发了这样的观点：旨在恢复胃肠道免疫稳态的口服免疫调节佐剂也可能有助于治疗炎症相关的结直肠癌（CRC）。在初步研究中，短期口服 TGF¿/ATRA 粒子疗法导致 APCMin/+ 小鼠中已形成的息肉显着消退，这提供了强有力的概念证明。基于这些数据，在自发性肠息肉病和癌变的小鼠模型中评估了两种不同的治疗策略：a) 原位 Treg 生成和 b) 直接抑制肿瘤促进炎症效应物。更具体地，在目标1中，在APCMin/+小鼠模型的两个不同实施方案中测试了口服缓释TGFβ/ATRA纳米颗粒实现长期根除已建立的自发性腺瘤和腺癌的能力。在 Aim 2 中，在相同的模型中评估了针对促肿瘤炎症 T 细胞/肥大细胞轴的口服纳米佐剂，即抗 IL-9 抗体和马赛替尼的控释制剂。如果成功，这些研究可以为结直肠癌的治疗带来新的治疗模式。