Oral Immune Modulatory Adjuvants for Treatment of Colorectal Carcinoma

描述（由申请人提供）：调节性T细胞（Treg）的连续转移可诱导肠息肉病和癌的小鼠模型中的肿瘤消退，揭示了Treg在控制肠道中促肿瘤炎症中的重要作用。另外，PI实验室的研究表明，口服缓释TGF ²和全反式维甲酸（ATRA）制剂（胃肠道（GI）中粘膜Treg生成的两种必需介质）可以有效抑制炎症性肠道疾病（IBD）小鼠模型中的疾病症状。这些发现引起了这样一种观点，即旨在恢复胃肠道免疫稳态的口服免疫调节佐剂也可用于治疗炎症相关的结直肠癌（CRC）。在最初的研究中，短期口服TGF β/ATRA粒子治疗导致APCMin/+小鼠中已建立的息肉的显著消退，提供了强有力的概念验证。基于这些数据，在自发性肠息肉病和癌发生的鼠模型中评估了两种不同的治疗策略，所述治疗策略靶向：a）原位Treg产生和B）直接抑制促肿瘤炎性效应物。更具体地，在目的1中，在APCMin/+小鼠模型的两个不同实施方案中测试口服缓释TGF β/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。在目的2中，在相同的模型中评估靶向促肿瘤发生炎性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。如果成功的话，这些研究可以为CRC的管理带来新的治疗模式。 公共卫生相关性：结直肠癌（CRC）是美国癌症相关死亡的第三大原因，与结肠中的慢性炎症活动有关。目前靶向肿瘤促进炎症的治疗方法仅限于高危人群，因为大多数抗炎剂会引起严重的副作用。该提案将测试用于控制促肿瘤发生炎症活性的新策略，即免疫调节小分子药物/细胞因子组合的新型口服控释制剂，如果发现有效，则有可能在CRC管理中引入新的治疗模式。

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. PUBLIC HEALTH RELEVANCE: Colorectal cancer (CRC), the third leading cause of cancer-related death in the US, has been linked to chronic inflammatory activity in the colon. Current therapeutic approaches targeting tumor-promoting inflammation are limited to high-risk groups as the majority of anti-inflammatory agents cause severe side-effects. This proposal will test a new strategy for controlling pro-tumorigenic inflammatory activity, i.e. novel oral controlled-release formulations of immune-modulatory small molecule drug/cytokine combinations, which if found effective have the potential to introduce a new therapeutic paradigm in the management of CRC.