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Usurping TIGIT and CD73 activities with responsive, genetically-engineered NK cells as immunotherapy for glioblastoma

利用反应性基因工程 NK 细胞取代 TIGIT 和 CD73 活性作为胶质母细胞瘤的免疫疗法

基本信息

批准号：
10318207
负责人：
Sandro Matosevic
金额：
$ 20.78万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-11 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318207
关键词：
Ablation Adenosine Adoptive Cell Transfers Adoptive Transfer Allogenic Antibodies Antitumor Response Architecture Binding Blood - brain barrier anatomy Brain Neoplasms Caring Cells Clinical Clinical Treatment Cytolysis Data Development Diagnosis Disease Effector Cell Engineered Gene Engineering Functional disorder Generations Genetic Engineering Glioblastoma Goals Growth Human Human Engineering Hypoxia Immunoglobulin Fragments Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In Vitro Infiltration Ligands Malignant neoplasm of brain Mediating Modality Natural Killer Cells Output Pathogenesis Pathology Patients Phenotype Route Safety Signal Transduction Stimulus System T-Lymphocyte Toxic effect Translating Translations Tumor Immunity Ursidae Family Work Xenograft procedure anaerobic glycolysis base chemokine chimeric antigen receptor clinical translation cytokine cytotoxicity engineered NK cell extracellular genetic element improved in vivo innovation notch protein novel overexpression poliovirus receptor prognostic value programs receptor recruit response synergism trafficking tumor tumor hypoxia tumor microenvironment

项目摘要

SUMMARY Glioblastoma (GBM) is an extremely aggressive brain cancer, with fewer than 5% of patients surviving to 5 years after diagnosis. The GBM microenvironment fuels its pathogenesis through the expression of CD155, which drives inhibition of NK cell effector functions via its ligand TIGIT, and the hypoxia-driven generation of adenosine from ectoenzyme CD73. Adenosine, in turns, impairs the anti-tumor function of natural killer (NK) cells. As a result, GBM immunotherapies with adoptively-transferred NK cells can be subject to severe immunosuppression. In order to improve the treatment of GBM, this proposal describes the development of a novel immunotherapy with NK cells engineered to co-target, in a responsive manner, the inhibitory functions of TIGIT and CD73. We propose to do so by engaging synthetic notch signaling to usurp TIGIT binding on NK cells and trigger the local release of CD73 antibody fragments. We will characterize the anti-tumor function and GBM infiltration of these cells in orthotopic GBM xenografts and make a case for the use of these allogeneic engineered cells as a safe, powerful immunotherapeutic modality. The highly translational project proposes to develop curative new immunotherapies for GBM which have the potential to be be translated into effective clinical treatments in humans.

总结胶质母细胞瘤（GBM）是一种极具侵袭性的脑癌，只有不到5%的患者存活至诊断后5年。GBM微环境通过表达CD 155，其通过其配体TIGIT驱动NK细胞效应子功能的抑制，以及低氧驱动的腺苷来自胞外酶CD73。腺苷反过来削弱自然杀伤细胞（NK）的抗肿瘤功能细胞因此，采用过继转移NK细胞的GBM免疫疗法可能会受到严重的影响免疫抑制为了改善GBM的治疗，该提案描述了一种使用NK细胞的新型免疫疗法，所述NK细胞经工程改造以响应性方式共同靶向以下抑制功能： TIGIT和CD73。我们建议通过参与合成notch信号传导以篡夺NK细胞上的TIGIT结合来实现这一点。并触发CD73抗体片段的局部释放。我们将描述抗肿瘤功能和GBM 这些细胞在原位GBM异种移植物中的浸润，并为使用这些同种异体工程细胞作为一种安全，强大的免疫方式。这个高度平移的项目提出，开发治疗GBM的新免疫疗法，这些疗法有可能转化为有效的临床治疗。人类的治疗。