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.

Dual functional immunostimulatory polymeric prodrug carrier with pendent indoximod for enhanced cancer immunochemotherapy

2019 Fall National Meeting

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