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（通过应用提供）：T调节细胞（TREG）的产物转移可以在肠道息肉病和癌的鼠模型中诱导肿瘤消退，这揭示了Treg在控制肠道中促进肿瘤感染中的重要作用。另外，对PI实验室的研究表明，口服持续释放的TGF研讨会和全反式视黄酸（ATRA）配方，这是胃肠道（GI）的两个基本粘膜Treg产生的基本介质，可以导致在炎症性弓形病（IBD）炎症模型中有效抑制疾病症状的有效抑制（IBD）。这些发现引起了这样的观念：旨在恢复胃肠道免疫稳态的口服免疫调节佐剂也可能在治疗与炎症相关的结直肠癌（CRC）的治疗中有用。在最初的研究中，短期口服TGF¿ /ATRA粒子疗法导致对APCMIN /+小鼠中既定的息肉进行了巨大的回归，从而提供了强大的概念验证。基于这些数据，针对的两种不同的治疗策略：a）原位treg产生和b）在自发性肠道息肉病和致癌作用的鼠模型中评估了直接抑制促肿瘤炎症作用的。更具体地说，在AIM 1中，在APCMIN /+小鼠模型的两个不同的实施例中测试了口服持续释放TGF。在AIM 2中，在同一模型中评估了针对抗氧化型炎症性T细胞/肥大细胞轴的口服纳米助剂，即抗IL-9抗体和马斯替尼的受控释放公式。如果成功，这些研究可能会导致CRC管理中的新治疗范式。