IMMU-23. TARGETING THE CD200 CHECKPOINT TO ENHANCE IMMUNOTHERAPY FOR CNS TUMORS

Abstract Numerous clinical trials targeting immune checkpoints have failed to enhance survival in patients with CNS tumors. We are targeting a unique checkpoint, CD200, which controls the immune system through paired inhibitory and activation receptors. The CD200 checkpoint interferes with tumor-immune interactions through secretion of CD200 from tumors inducing an immunosuppressive environment and up regulation of CD200 in tumor-associated vascular endothelial cells, creating an immunological blood brain barrier. We are targeting the activation receptor with a peptide ligand (CD200AR-L) that activates antigen-presenting cells and enhances dendritic cell maturation, resulting in antigen specific T cell cytokine production. Directing the immune system requires introduction of an antigen such as autologous or allogeneic brain tumor lysate for non-immunogenic tumors such as CNS tumors. Treatment with CD200AR-L significantly extends survival in two murine glioma models. Additionally, an ongoing pilot study treating companion dogs with high-grade glioma using a canine specific CD200 peptide ligand in combination with an autologous tumor lysate vaccine increased median survival to 330 days, compared to 194 days with lysate alone. Currently, 41% of the dogs are alive; the longest living dog is now 810 days post-surgery. 28% of dogs died of non-tumor related deaths. In contrast, 100% of the dogs in the tumor lysate-only group died of tumor recurrence. We have developed human CD200 peptide ligands that enhance cytokine secretion, dendritic cell maturation, and antigen-specific immune response in vitro. In addition, we have shown that a ligand targeting the activation receptor (CD200AR-L) results in down regulation of PD-1. We have also demonstrated that the use of a CD200AR-L resulted in a significant survival benefit in a murine breast carcinoma model. In this light, CD200AR-L may be a powerful immunotherapy platform for other solid tumors. This innovative research may provide a significant breakthrough for the field of cancer immunotherapy.