Work

Cadd-14. Targeting the Cd200 Checkpoint for the Fight Against Central Nervous System Tumors

Year: 2018

Type: article

Abstract: Numerous ongoing 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 multiple mechanisms: i) CD200 is secreted from tumors inducing an immunosuppressive environment, ii) CD200 is upregulated in tumor-associated vascular endothelial cells, creating an immunological barricade around the tumor microenvironment. We are targeting the activation receptor with a peptide ligand (CD200AR-L) activates antigen-presenting cells, enhancing dendritic cell maturation, cytokine production and antigen specific T cell activation. Treatment with CD200AR-L significantly extends survival in two murine glioma models. Directing the immune system to “fight the tumor”, requires introduction of an antigen such as autologous or allogeneic tumor lysate for non-immunogenic tumors such as CNS tumors. In an ongoing pilot study treating companion dogs with high-grade glioma, patients receiving a canine specific CD200 peptide inhibitor in combination with the autologous tumor lysate vaccine increased median survival to 330 days, compared to 194 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. Furthermore, serum chemistry profiles and physical examinations showed that the peptide did not induce any systemic toxicity. Importantly, we have developed human CD200 peptide ligands that enhance cytokine secretion, dendritic cell maturation, and antigen-specific immune response. This innovative research may provide a significant breakthrough for the field of cancer immunotherapy. We have also demonstrated that the use of a CD200AR-L in a murine breast carcinoma model resulted in a significant survival benefit. In this light, CD200AR-L may be a powerful immunotherapy platform for other solid tumors.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noy148.1159