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Targeting Lag-3 and PD -1 in Myeloid Cells of GBM

靶向 GBM 骨髓细胞中的 Lag-3 和 PD -1

基本信息

批准号：
10367804
负责人：
Michael Lim
金额：
$ 40.28万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367804
关键词：
Ablation Adoptive Transfer Adult Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response Binding Biological Assay Blood Blood specimen Bone Marrow Brain Neoplasms CTLA4 gene Cells Cellular Assay Clinical Clone Cells Coculture Techniques Congenic Mice Correlative Study Data Flow Cytometry Funding Future Glioblastoma Glioma Histology Human Immune Immune checkpoint inhibitor Immune response Immune system Immunosuppression Immunotherapy Infiltration Investigation Ions Knockout Mice Knowledge Laboratories Long-Term Survivors Magnetic Resonance Imaging Malignant neoplasm of brain Malignant neoplasm of lung Measures Mediating Metabolic Mus Mutation Myelogenous Myeloid Cells Myeloid Progenitor Cells Myeloid-derived suppressor cells PD-1 blockade PTPRC gene Patients Peripheral Phase I Clinical Trials Phenotype Prognosis Progression-Free Survivals Recurrence Renal Cell Carcinoma Resistance Role Sampling Site Solid Neoplasm Surface T cell clonality T cell response T-Cell Activation T-Lymphocyte T-cell receptor repertoire Testing Therapeutic Time Translating Tumor Antigens Tumor Expansion Wild Type Mouse anti-CTLA4 anti-PD-1 anti-PD1 antibodies anti-PD1 therapy anti-cancer anti-tumor immune response cancer type combinatorial cytotoxicity design draining lymph node effector T cell exhaustion extracellular functional improvement immune checkpoint blockade improved in vivo inflammatory milieu insight macrophage melanoma monocyte mouse model neoantigens neoplastic cell novel peripheral blood phase I trial pre-clinical prevent programmed cell death protein 1 radiological imaging recruit response single cell sequencing standard of care success tumor tumor progression tumor-immune system interactions

项目摘要

Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumor in adults. GBM has a bleak prognosis of approximately 12-15 months, despite continuing advances to the standard of care. Immunotherapy has demonstrated the significant potential to boost immune responses against many cancer types; inhibitors of checkpoint molecules, such as CTLA-4 and PD-1, have been used to treat many solid tumors with varying success. While it has demonstrated efficacy in treating some tumors with an inflammatory milieu and high degree of infiltration by anti-tumor T cells, it has shown little to no response in treating tumors such as GBM. This tumor type is characterized by a particularly immunosuppressive microenvironment with a notable paucity of T cells. Targeted approaches designed to reduce immunosuppression in the tumor and increase anti-tumor T cell activity are crucial to successfully treat GBM. Recent preclinical data from our laboratory and preliminary findings from a Phase I clinical trial have shown promising signs of efficacy with co-blockade of PD-1 and the alternative checkpoint LAG-3. We have observed long-term survivors and radiographic responses in trial patients. We have noted improved T cell responses against the tumor and a reduction in myeloid-derived suppressor cells (MDSCs), following dual therapy of patients. We propose to study the mechanism by which the immune system is enhanced against GBM via PD-1/LAG-3 blockade. We hypothesize that dual therapy recruits cells of the myeloid compartment in order to boost anti-cancer T cell activity, and reduces the presence of immunosuppressive myeloid cells in the tumor itself. To test our hypothesis, we will investigate the: i) priming of T cells by antigen presenting myeloid cells in response to dual therapy in murine models of GBM, ii) role of soluble product generated from cleavage of surface LAG-3 molecule in inducing myeloid-mediated immunosuppression in the tumor (using both murine models and patient samples), and iii) expansion of anti-tumor T cells and reduction in MDSCs levels in patients following dual therapy. We will correlate our findings with overall survival and progression free survival of the trial patients. We expect that the data generated from these studies will provide novel insights into a previously unexplored mechanism by which dual immune checkpoint blockade therapy can modulate the myeloid response against tumors. The knowledge obtained from this study will contribute to improving the design of future therapeutic strategies to treat GBM patients.

胶质母细胞瘤（GBM）是世界上最具侵袭性的原发性恶性脑肿瘤