Oral Immune Modulatory Adjuvants for Treatment of Colorectal Carcinoma

口服免疫调节佐剂治疗结直肠癌

基本信息

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
项目类别：
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

项目摘要

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，揭示了Treg在控制肠道中促进肿瘤的炎症方面的重要作用。实验室证明口服缓释TGF¿和全反式视黄酸 (ATRA) 制剂是胃肠道 (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。提出了这样一种观点：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）。研究短期口服 TGF¿ /ATRA 粒子疗法导致 APCMin/+ 小鼠中已形成的息肉显着消退，提供了强有力的概念证明。基于这些数据，两种不同的治疗策略针对：a) 原位 Treg 生成和 b) 直接抑制肿瘤。 -促进炎症效应物，在自发性肠息肉病和致癌的小鼠模型中进行评估，更具体地说，在目标 1 中评估口服缓释 TGF 的能力。在 APCMin/+ 小鼠模型的两个不同实施方案中测试了 /ATRA 纳米颗粒实现长期根除已形成的自发性腺瘤和腺癌的效果，该纳米佐剂靶向促肿瘤炎症 T 细胞/肥大细胞轴，即受控。 - 在相同的模型中评估抗 IL-9 抗体和马赛替尼的释放制剂如果成功，这些研究可以带来新的治疗范例。 CRC 的管理。