IMMU-11. TARGETING THE CD200 CHECKPOINT BLOCKADE: A NEW DIRECTION FOR IMMUNOTHERAPY

Abstract

Glioblastoma multiforme is an incurable primary brain tumor. The standard of care consists of resection followed by radiation and chemotherapy is associated with a median overall survival of 14.6 months. To address this dismal outcome, aggressive interventions need to be pursued. Recently, the FDA approved immune checkpoint inhibitor therapy for solid tumors that are otherwise refractory to standard therapy heralding a new era for effectively treating cancer. Yet, immune checkpoint inhibitors yield poor responses for patients with glioblastoma, calling into question whether cancer immunotherapy can be applied to glioblastoma. We have recently reported that inhibiting an alternative immune checkpoint, CD200, inhibits tumor-induced immunosuppression without toxic side effects. CD200 protein suppresses immune activation after engaging the CD200 inhibitory receptor, which is restricted to immune cells. We have previously shown that C200 is expressed in malignant brain tumors and is an important barrier to effective immunotherapy. By exploring peptide fragments resulting from protease cleavage of the CD200 protein, we observed that CD200 actually functions through paired receptors and that certain peptide ligands (CD200 inhibitor) actually surmount the immunosuppressive effects of CD200 to stimulate immune response. This was validated in glioma murine models. We recently developed humanized CD200 inhibitors, which was verified in vitro measuring the immune response of human cells to CMV antigen (pp65495-503). We conducted a clinical trial in companion dogs with primary gliomas and showed that canine-specific CD200 inhibitor. In this ongoing clinical trial using dogs diagnosed with high-grade glioma, receiving a canine specific CD200 inhibitor in combination with the autologous tumor lysate vaccine had enhanced survival up to 615 days, relative to 214 days with lysate alone, without any observed toxicity or signs of reoccurrence. As a result of these findings, we believe that is important to move forward with phase I human clinical trials utilizing inhibitor peptidomimetics.