(391h) Dual Functional Immunostimulatory Polymeric Prodrug Carrier with Pendent Indoximod for Enhanced Cancer Immunochemotherapy

Immunotherapy has been regarded as one of the most promising approaches towards many types of cancers. Indoleamine 2,3-dioxygenase (IDO) has emerged as an important immuno-oncology target due to its role in driving the immune suppressive tumor microenvironment. As a clinically studied IDO inhibitor, indoximod (IND) represents a very promising agent for cancer immunotherapy. However, poor solubility and limited delivery efficiency hinder its application. Furthermore, IND demonstrates limited clinical benefits in solid tumors as a single drug due to its insufficient tumor immunogenicity. In order to achieve enhanced antitumor activity, a cleavable IND-based prodrug polymer (POEG-b-PVBIND), consisting of hydrophilic poly (oligo (ethylene glycol) methacrylate) (POEG) blocks and a number of pendent hydrophobic IND segments, has been rationally designed for co-delivery of those hydrophobic agents that can elicit immunogenic cell death (ICD). In our studies, POEG-b-PVBIND prodrug polymer alone was able to form spherical micelles with a diameter around 20 nm, and well retained the pharmacological activity of IND either in modulating tumor microenvironment or inhibiting tumor growth in an aggressive murine breast cancer model (4T1.2). ICD-triggered agents, such as doxorubicin (Dox), sunitinib (Sun), and daunorubicin (Dau), can be formulated in POEG-b-PVBIND-based micelles. Using Dox as a model drug, DOX/POEG-b-PVBIND formulation have exhibited more potent antitumor activity in vivo compared to POEG-b-PVBIND micelles and DOX formulated in a pharmacologically “inert” nanocarrier, POEG-b-PVB micelles. Our studies have demonstrated that released Dox can kill the tumor cells and stimulate immune response by promoting IFN-γ producing CD8⁺ T cells infiltration. Meanwhile, cleaved IND significantly increased CD8⁺ T cell infiltration and reduced immunosuppressive T regulatory cells, confirming synergistic effect of indoximod and Dox for the overall improved antitumor activity. These results suggest that IND-based polymeric prodrug micelles may serve as a dual functional carrier for improved immuno-chemotherapy.