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.
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.
| Chung, Allen Y; Li, Qingsheng; Blair, Sarah J et al. (2014) Oral interleukin-10 alleviates polyposis via neutralization of pathogenic T-regulatory cells. Cancer Res 74:5377-85 |
