Research Project
9565867
Recent FDA approvals of ipilimumab, nivolumab, and pembrolizumab, which target checkpoint receptors cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), have ushered in a new era of cancer immunotherapy in metastatic melanoma. Despite unprecedented overall survival benefits with combination therapy, the incidence of complete responses are only 12-22%, immune-related adverse events (irAEs) are increased, and the cost of treatment is approaching $275,000 per patient per year. As such, cost-effective approaches to improve the safety and effectiveness of checkpoint blockade for not only metastatic melanoma, but also for more genetically stable solid tumors are needed. Cell adhesion integrins VLA-4 and LFA-1 are required for efficient antigen presentation, trafficking, and tumoricidal activity of effector cells. These integrin receptors are clinically validated therapeutic targets in autoimmune disease; inhibitors such as natalizumab decrease T-cell activation and migration. Conversely, we have discovered small molecule integrin agonists, eg, 7HP349, that may increase the efficiency of the immune response against solid tumors. This approach could be particularly useful when combined with immune checkpoint blockade. Completed phase I studies have demonstrated that 7HP349 can significantly enhance the anti-tumor activity of anti-CTLA- 4, anti-PD-1, and anti-4-1BB antibodies in animal models of melanoma and carcinoma. Toxicity studies have demonstrated the compound to be safe, even when administered at doses up to 80-fold higher that it?s therapeutic dose. Based on this success, our current phase II effort is centered around in vivo testing of oral administration of 7HP349 in the B16-BL6 melanoma model, mechanistic studies to guide biomarker development, including the effects of 7HP349 on T effector cell biodistribution (Specifc Aim 1), GLP IND- enabling studies of toxicity in rodent and non-rodent species, including radiolabeled ADME (Specific Aim 2), and an iterative synthetic chemistry approach to further optimize drug like characteristics of our lead candidate 7HP349 (Specific Aim 3). All work proposed will be consistent with FDA guidelines outlined in ?Guidance for Industry: S9 Nonclinical evaluation of anticancer pharmaceuticals.?
