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Fgl-2 targeted therapy for reversing multi-modality immune suppression

Fgl-2靶向治疗逆转多模式免疫抑制

基本信息

批准号：
9152967
负责人：
Amy Beth Heimberger
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9152967
关键词：
ADORA2A gene Adenosine Adenosine A2B Receptor Antibodies Autologous Biological Biological Assay Biological Markers Blocking Antibodies Blood CD3 Antigens CD80 gene Cd68 Cell Line Cell Maturation Cells Cessation of life Complex Cytotoxic T-Lymphocyte-Associated Protein 4 Cytotoxic T-Lymphocytes Data Dendritic Cells Detection Development Endothelial Cells Engineering Family Fibrinogen Future Gene Expression Gene Expression Profiling Generations Genetic Engineering Glioma Goals Growth Health Human ITGAX gene Immune Immune response Immunologic Surveillance Immunosuppression Immunosuppressive Agents Immunotherapy Knockout Mice Lead Longevity Lymphocyte Activation MHC Class II Genes Malignant Neoplasms Mediating Messenger RNA Modality Molecular Monoclonal Antibodies Monoclonal Antibody Therapy Mus Myelogenous Neuraxis Neurologic Normal tissue morphology PDCD1LG1 gene PECAM1 gene Pathway interactions Patients Peptides Play Population Proteins Publishing Regulation Reporter Genes Role Serum Solid Neoplasm Suppressor-Effector T-Lymphocytes System T-Cell Activation T-Cell Proliferation T-Lymphocyte Technology Testing Therapeutic Time Tissues Transforming Growth Factor beta Treatment Failure base chemotherapy clinical application cytokine liquid biopsy mRNA Expression macrophage melanoma mouse model neoplastic cell novel overexpression polyclonal antibody response standard of care targeted treatment temozolomide treatment response tumor tumor growth

项目摘要

Our goal of this application is to test the hypothesis that blocking the newly identified immune suppressive regulator fibrinogen-like protein 2 (Fgl2) in GBM will comprehensively reverse tumor-mediated immune suppression thereby allowing immunological clearance of gliomas within the central nervous system. We have discovered that Fgl2 is highly expressed in GBM tissues(recently published by JNCI). Patients with GBM tumors that have high levels of Fgl2 expression have a statistically shorter overall survival time relative to those with low expression levels. As further proof of concept, Fgl2-engineered GBM tumors progressed rapidly with neurological sequela and death when compared to the reporter gene-GFP-engineered GBM cells in syngeneic mice. Our data shows that Fgl2 is a key immune suppressive hub that correlates with immune checkpoint family expression (PD-L1, PD-1, and CTLA-4), immune suppressive cytokines (TGF-β), and glioma-infiltrating, of immunosuppressive immune populations such as myeloid-derived suppressor cells (MDSCs), Tregs and M2 macrophages. One underlying mechanism for this observation is Fgl2 induced CD39 and CD73 in T cells. The CD39 protein converts ATP to ADP and AMP, which is then converted to adenosine by CD73. Adenosine is an immunosuppressive metabolite that then suppresses T lymphocyte activation and effector function. Furthermore, the CD39/CD73 complex enhances the conversion of M1 into tumor-promoting M2 to promote tumor growth. Based on these data, we have created a first generation antibody that blocks Fgl2 immune suppressive activity and increases median survival in murine models with established intracerebral gliomas. To test our central hypothesis for this application, the following aims are proposed: Aim 1: Determine the association of Fgl2 expression with immune suppression in human GBM and investigate the mechanism of CD39/CD73 expression in different types of immune cells in GBM; Aim 2: Select the most therapeutically efficacious cross-species Fgl2 mAb that promotes antitumor immune response. Impact: This study will yield a therapeutic candidate – a Fgl2 blocking antibody that may reverse tumor- mediated immune suppression and the number of immune suppressive cells in GBM. Considering that Fgl2 can be detected in almost all GBMs, with most having very high levels, such a candidate therapeutic will be important. This study will also further mechanistically elucidate how Fgl2 regulates immune suppressive gene expression in immune suppressive cells and within effector immune populations. Finally, this study will show whether detection of Fgl2 in circulating GBM tumor cells (CTC) using our newly invented universal CTC capture technology (PCT/US2014/020615) will correlate with the level of GBM tumor Fgl2 expression as a biomarker for guiding blocking therapy in the future. This type of assay would also be highly significant as a longitudinal liquid biopsy for gene expression analysis that could be used in the context of multiple clinical applications such as early progression/treatment failure and response to treatment.

我们这一应用的目的是测试假设，阻断新发现的免疫抑制