Michael Olin,
Associate Professor
I have dedicated my career to developing immunotherapy for pediatric brain tumors. We, among others, have utilized tumor cells as vaccine components, demonstrating promising results with minimal toxicity. However, progression to a productive immune response necessitates passing a number of immunological checkpoints that act as barriers to effective immunotherapy because of “self” antigen recognition. Our primary research is focused on the CD200 immune checkpoint, which modulates the immune system through paired receptors, i.e., an inhibitory receptor (CD200R1) and four activation receptors (CD200AR) in mice, two in humans. We developed a strategy to engage the CD200AR with a peptide ligand (CD200AR-L), which improved survival in breast and glioma murine models when used with tumor lysates (TL) to direct an anti-tumor response. Moreover, in dogs bearing spontaneous high-grade glioma receiving a canine-specific CD200AR-L, administered concomitantly with autologous TL, we showed a 43% 3-year progression-free survival, enhancing the median survival to 18 months as compared to 6 months in dogs receiving lysates alone. No toxicity or immune-related adverse effects were observed. We suggest that these unprecedented responses are due to CD200 acting as a “master regulator” for multiple immune checkpoints. Our preliminary studies showed that CD200AR-L overcomes the suppressive effects of CD200 and PD-L1, which are both shed by tumors, by downregulating the inhibitory CD200R1 and PD-1, on both antigen presenting cells (APC) and T cells, and PD-L1 on APCs, through the activation of the DAP10/12 pathways. We now derived a humanized peptide inhibitor in a GMP facility and are submitting an IND for an upcoming Phase I trial.
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