Local Delivery of CTLA-4 Blockade Inhibits Growth of Pancreatic Tumors

Immune checkpoint blockade has demonstrated great potential in activating antitumor immunity. Ipilimumab is a monoclonal antibody which targets cytotoxic T-lymphocyte antigen-4. CTLA-4 belongs to the CD28 class of receptors and is found on the surface of CD4+ and CD8+ T cells. CTLA-4 acts to suppress the immune system when bound to CD80 and CD86 receptors on antigen presenting cells. Ipilimumab, or anti-CTLA-4, has shown to be effective in significantly extending the survival of patients with metastatic melanoma. However, systemic delivery of Ipilimumab also induces significant side effects such as: colitis, dermatitis, uveitis, and hypophysitis. In order to minimize toxicity, we and others have hypothesized that intratumoral administration of anti-CTLA-4 at a lower dose can have the same antitumor efficacy as systemic delivery but without the toxicity. This work begins with an investigational pilot study to determine the efficacy of anti-CTLA-4 by delivering 60 µg of anti-CTLA-4 to a group of mice and measuring the tumor growths when compared to an untreated control group. Once efficacy had been demonstrated, a dosing study was conducted to identify an optimal intratumoral dosage delivered to murine models. The groups were given doses of either 30 µg, 60 µg, or 120 µg. From this study, the 60 µg group had the lowest average tumor size of 300 mm3. Our lab has previously demonstrated that IL-12 co-formulated with chitosan has demonstrated prolonged intratumoral retention therefore, 60 µg of anti-CTLA was co-formulated with a chitosan solution investigate the efficacy in a delivery vehicle. Finally, 60 µg of anti-CTLA-4 was delivered in a proprietary hydrogel alone and with Interleukin-12 to examine the effects of controlled release