Fgl2 neutralizing therapy for inducing tumor specific brain resident immune memory against CNS tumor relapse

Fgl2中和疗法诱导肿瘤特异性脑常驻免疫记忆对抗中枢神经系统肿瘤复发

基本信息

批准号：
10655501
负责人：
Amy Beth Heimberger
金额：
$ 58.95万
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：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655501
关键词：
Antibodies Antibody Therapy Biological Brain Brain Neoplasms CAR T cell therapy CD3 Antigens CXCL1 gene Cause of Death Cd68 Cell Maturation Cell Therapy Cell physiology Cell secretion Cells Central Nervous System Central Nervous System Neoplasms Cessation of life Clinical Collaborations Cytomegalovirus Data Death Domain Dedications Dendritic Cells Development Effector Cell Endothelial Cells Exposure to Fibrinogen Future Glioblastoma Glioma Goals Health Human ITGAX gene Immune Immunocompetent Immunoglobulin Fragments Immunologic Memory Immunology Immunosuppression Immunotherapy Injections Intracranial Neoplasms Knock-out Knockout Mice Laboratories Lipopolysaccharides Longevity Macrophage Mediating Membrane Memory Modeling Mus Nature PECAM1 gene Paper Patients Peptides Peripheral Phase Preparation Prevention Proteins Publishing Recurrence Recurrent tumor Regulatory T-Lymphocyte Relapse Research Role Safety Signal Transduction Solid Neoplasm Source T cell therapy T-Cell Activation T-Cell Proliferation T-Lymphocyte TP53 gene Testing Tissues Translations Transplantation Treatment Efficacy Treatment Failure Tumor Promotion Veins cell motility chemotherapy cytokine cytokine therapy efficacy evaluation immune checkpoint blockade immune clearance improved in vivo neoplastic cell neutralizing antibody next generation novel polyclonal antibody prevent programmed cell death ligand 1 residence standard care subcutaneous therapeutic candidate tissue resident memory T cell transcriptome sequencing tumor tumor growth tumor progression

项目摘要

Our goal in this application is to test the hypothesis that neutralizing the newly identified immune-suppressive regulator fibrinogen-like protein 2 (Fgl2) in glioblastoma (GBM) following standard care chemotherapy will trigger tumor-specific resident memory T cells in the brain (bTrm cells), which allows immunological clearance of gliomas within the central nervous system and prevention of GBM recurrence. This hypothesis was raised based on our recently published papers and newly established preliminary data. In brief, we have discovered that Fgl2 is highly expressed in GBM tissues (Yan et al, JNCI, 2015) and can transform low-grade brain tumors to GBM (Latha et al, JNCI, 2018). Knockout of Fgl2 in tumor cells completely eliminates tumor progression in the brains of immune-competent mice but not in immune-deficient mice (Yan et al, Nat Commun, 2019). Our unpublished preliminary data have shown that neutralizing Fgl2 via administering T cells armed with a membrane-anchored anti-Fgl2 scFv induces bTrm cells that reject intracranial tumor cell challenge directly or after intracranial transplantation into naïve mice (see preliminary data section); the same mice are unable to reject tumors from peripheral tissue challenge. To test our central hypothesis, the following aims are proposed: Aim 1: Determine how T-aFgl2– neutralizing T-cell therapy induces bTrm cells in brains; Aim 2: Optimize the T-aFgl2–neutralizing cell therapy and develop a next-generation T-aFgl2 cell therapy for boosting safety and therapeutic efficacy. Impact: This study will yield a therapeutic candidate—an Fgl2-neutralizing cell therapy that may permanently prevent tumor recurrence—the key deadly cause of GBM patient death. Considering that Fgl2 can be detected in almost all GBMs, with most having very high levels, this candidate therapeutic will be important. This study will also further mechanistically elucidate how Fgl2-neutralizing cell therapy induces bTrm cells and how we can make additional improvements to move this therapy into the next phase. Ultimately, this novel field will transform the treatment of GBM.

我们在此应用中的目标是测试中和新发现的免疫抑制的假设标准护理化疗后会触发胶质母细胞瘤 (GBM) 中的调节纤维蛋白原样蛋白 2 (Fgl2) 大脑中的肿瘤特异性常驻记忆 T 细胞（bTrm 细胞），可实现免疫清除这一假设是基于中枢神经系统内的胶质瘤和预防 GBM 复发而提出的。根据我们最近发表的论文和新建立的初步数据，我们发现了 Fgl2。在 GBM 组织中高表达 (Yan et al, JNCI, 2015)，可以将低级别脑肿瘤转化为 GBM （Latha 等人，JNCI，2018）。敲除肿瘤细胞中的 Fgl2 可完全消除大脑中的肿瘤进展。免疫功能正常的小鼠，但免疫缺陷的小鼠则不然（Yan 等人，Nat Commun，2019 年）。初步数据表明，通过施用带有膜锚定的 T 细胞来中和 Fgl2 抗 Fgl2 scFv 诱导 bTrm 细胞直接或在颅内注射后排斥颅内肿瘤细胞攻击移植到初始小鼠中（参见初步数据部分）；相同的小鼠无法排斥肿瘤周围组织挑战。为了检验我们的中心假设，提出了以下目标：目标 1：确定 T-aFgl2– 中和 T 细胞疗法诱导大脑中的 bTrm 细胞；目标 2：优化 T-aFgl2 中和细胞疗法并开发下一代 T-aFgl2 细胞疗法，以提高安全性和治疗效果。影响：这项研究将产生一种候选治疗药物——一种 Fgl2 中和细胞疗法，可能会考虑到 Fgl2 可以预防永久性肿瘤复发——GBM 患者死亡的关键致命原因。在几乎所有 GBM 中都能检测到，其中大多数的水平非常高，因此这种候选疗法将非常重要。这项研究还将进一步机械地阐明 Fgl2 中和细胞疗法如何诱导 bTrm 细胞和我们如何做出额外的改进，使这种疗法进入下一阶段，最终进入这个新领域。将改变 GBM 的治疗。