Oral Immune Modulatory Adjuvants for Treatment of Colorectal Carcinoma

描述(申请人提供)：过继转移T调节细胞(Treg)可以在小鼠肠息肉和癌症模型中诱导肿瘤消退，揭示Treg在控制肠道促癌炎症方面的重要作用。另外，Pi实验室的研究表明，口服缓释转化生长因子和全反式维甲酸(ATRA)制剂--胃肠道(GI)粘膜产生Treg的两种基本介质--可以有效抑制炎症性肠病(IBD)小鼠的疾病症状。这些发现提出了一种观点，即旨在恢复胃肠道免疫动态平衡的口服免疫调节佐剂也可能在治疗炎症相关性结直肠癌(CRC)中有用。在最初的研究中，短期口服转化生长因子/全反式维甲酸颗粒疗法导致APCMin/+小鼠已建立的息肉显著消退，提供了强有力的概念证据。基于这些数据，在自发性肠息肉和癌变的小鼠模型中，评估了两种不同的治疗策略：a)原位生成Treg和b)直接抑制促肿瘤炎症效应。更具体地说，在目标1中，在APCMin/+小鼠模型的两个不同实施例中测试了口服缓释转化生长因子/全反式维甲酸纳米粒实现对已建立的自发性腺瘤和腺癌的长期根除的能力。在AIM中，针对促肿瘤致炎T细胞/肥大细胞轴的2种口服纳米佐剂，即抗IL-9抗体和Masitinib的控释制剂，在相同的模型中进行了评估。如果成功，这些研究可以为结直肠癌的治疗带来新的范例。

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.