NOV 12, 2015 09:00 AM PST

Use of a CD200R Inhibitor to Overcome Central Nervous System Tumor Induced Immunosuppression

C.E. CREDITS: CE
Speakers
  • Assistant Professor, Department of Pediatrics, Division of Hematology/Oncology, University of Minnesota
    Biography
      For more than 7 years, I have dedicated my efforts to developing immunotherapy for 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 that necessitates passing a number of immunological checkpoints those act as barriers to effective immunotherapy because of "self" antigen recognition. The FDA-approved monoclonal antibodies ipilimumab, pembrolizumab and nivolumab, which inhibit the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD1) and programmed death 1 ligand (PD-L1) checkpoints, respectively, can be used to partially overcome this limitation. Both anti-CTLA-4 and anti-PD1 act directly on T cells, whereas a third immunological checkpoint acts directly on antigen-presenting cells, inducing T-cell tolerance. This checkpoint arises from the engagement of CD200 with its receptor (CD200R). CD200 is expressed in a variety of human tumors including melanoma and glioblastomas. However, it is the soluble form of CD200 that correlates with poor patient outcomes. CD200 has been well characterized as immunosuppressive in multiple graft rejection models, but prior to our work its role in tumor-induced immune suppression had not been clearly defined. We reported that CD200 concentration significantly increased in glioma patients' sera as their tumors progressed, correlating with increases in the lineage-negative myeloid-derived suppressor cell (MDSC) population. More surprisingly, we have found that CD200 is significantly upregulated on the vascular endothelial cells forming the blood-brain barrier in malignant human brain tissue but not in adjacent, apparently unaffected tissue. We are focusing our research on the development of a competitive CD200 inhibitor (a CD200R antagonist) with the goal of overcoming CD200-induced immune suppression. Our preliminary data show that the CD200R isoform activates antigen-presenting cells; we suggest that this occurs via a CD200R isoform that enhances chemokine and cytokine production required for the development of a tumoricidal response.

    Abstract:

    Cancer immunotherapy has demonstrated promising results. However, to date, researchers have failed to overcome the complex interplay between the immune system and the immune suppressive tumor microenvironment. Progression to a productive immune response involves passing a number of immunological checkpoints, which act as barriers for productive immunotherapies. To overcome this limitation, the FDA-approved monoclonal antibodies, ipilimumab, pembrolizumab and nivolumab, respectively, which inhibits the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD1) and programmed death 1 ligand (PD-L1) checkpoints. Both anti-CTLA4 and anti-PD1 act directly on T cells. In contrast, a third immunological checkpoint act directly on antigen presenting cells inducing T-cell tolerance. This checkpoint arises from the engagement of CD200 and it’s receptor (CD200R). CD200 is expressed in a variety of human tumors including melanoma and glioblastomas. However, it is the soluble form of CD200 that correlates with poor patient outcome. We reported that CD200 concentration significantly increased in the sera of glioma patients as their tumors progressed, which correlated with increased lineage negative myeloid derived suppressor cell (MDSC) population. We developed an inhibitor of the CD200 (CD200R antagonist) that acts directly on the CD200R on antigen presenting cells overpowering the suppressive properties of CD200. Our CD200R antagonist inhibits myeloid derived suppressor cell expansion, enhances cytokine and chemokine production significantly enhancing survival in both glioma and breast carcinoma tumor models.


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