Michael Olin,
Associate Professor,
University of Minnesota Masonic Cancer Center
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.
CD200-Expresson on Vascular Endothelial cells is Mediated Through VEGF
Tuesday, 18 February 2020 at 12:30
Add to Calendar ▼2020-02-18 12:30:002020-02-18 13:30:00Europe/LondonCD200-Expresson on Vascular Endothelial cells is Mediated Through VEGFCirculating Biomarkers World Congress 2020 in Coronado Island, CaliforniaCoronado Island, CaliforniaSELECTBIOenquiries@selectbiosciences.com
Central nervous system tumors are the number one killer of children with cancer. Among those, glioblastoma multiforme (GBM) is an incurable primary brain tumor. The standard of care consists of resection followed by radiation and chemotherapy using temozolomide and is associated with a median overall survival of 14.6 months. To overcome this dismal outcome, clinicians are turning to immunotherapy approaches, which have demonstrated promising results in other solid tumors. However, immunosuppression by the tumor microenvironment prohibits a durable anti-tumor response and the optimization of immunotherapy, especially in GBM. Tumors have capitalized on immune regulatory mechanisms that facilitate the inhibition of an immune response. The CD200 checkpoint includes the tumor-bound protein CD200 and its inhibitory receptor. We recently reported that CD200 is also expressed on tumor vascular endothelial cells and that this expression is upregulated by VEGF, creating an immunological barrier around the tumor microenvironment. CD200 is also shed by tumors, and it has been reported that this soluble CD200 interacts with its inhibitory receptor restricted to immune cells to create an immunosuppressive environment. However, as extracellular proteases are abundant in the sera, it is highly probable for the soluble CD200 to be degraded. We hypothesis is that tumor-derived extracellular vesicles modulate CD200-induced immunosuppression. There is abundant evidence in the literature that extracellular vesicles derived from tumors suppress antigen-specific and non-specific anti-tumor responses, mediating a broad array of detrimental effects on the immune system. We now know that tumor-derived extracellular vesicles contain CD200 and VEGF. In addition, others have reported that miR-150, which plays a role in tumorigenesis, interacts with TAMs to induce VEGF, suggesting a link between tumor-derived extracellular vesicles, and the upregulation of C200. We propose i) CD200-expressing tumor-derived extracellular vesicles induce immune suppression, ii) VEGFpos-tEVs upregulates CD200 on vascular endothelial cells and/or iii) miR150 interaction with tumor associated macrophage upregulate CD200 on vascular endothelial cells maintain an immune suppressive tumor microenvironment.
Add to Calendar ▼2020-02-17 00:00:002020-02-18 00:00:00Europe/LondonCirculating Biomarkers World Congress 2020Circulating Biomarkers World Congress 2020 in Coronado Island, CaliforniaCoronado Island, CaliforniaSELECTBIOenquiries@selectbiosciences.com
Add to Calendar ▼2020-02-18 12:30:002020-02-18 13:30:00Europe/LondonCD200-Expresson on Vascular Endothelial cells is Mediated Through VEGFCirculating Biomarkers World Congress 2020 in Coronado Island, CaliforniaCoronado Island, CaliforniaSELECTBIOenquiries@selectbiosciences.com
