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检验以下假设，即中和新确定的免疫抑制标准护理化疗后胶质母细胞瘤（GBM）中的调节纤维蛋白原样蛋白2（FGL2）将触发肿瘤特异性居民记忆T细胞（BTRM细胞），该细胞允许免疫清除中枢神经系统中的神经瘤和预防GBM复发。这个假设是基于在我们最近发表的论文和新建立的初步数据上。简而言之，我们发现FGL2 在GBM组织中高度表达（Yan等，JNCI，2015年），可以将低度脑肿瘤转化为GBM （Latha等，JNCI，2018）。肿瘤细胞中FGL2的敲除完全消除了大脑的肿瘤进展免疫能力小鼠，但不在免疫缺陷小鼠中（Yan等，Nat Commun，2019年）。我们未发表的初步数据表明，通过武装膜锚定的T细胞中和FGL2 抗FGL2 SCFV诱导直接或颅内后拒绝颅内肿瘤细胞挑战的BTRM细胞移植到幼稚的小鼠中（请参阅初步数据部分）；同一只老鼠无法拒绝外围组织挑战。为了检验我们的中心假设，提出了以下目的：目标1：确定T-AFGL2 –如何中和T细胞疗法诱导大脑中的BTRM细胞； AIM 2：优化T-AFGL2中和细胞治疗并开发下一代T-AFGL2细胞疗法，以提高安全性和治疗效率。影响：这项研究将产生治疗性候选者 - FGL2中和细胞疗法可能永久防止肿瘤复发，这是GBM患者死亡的主要致命原因。考虑到FGL2可以在几乎所有GBM中都可以检测到，大多数人具有很高的水平，这种候选疗法将很重要。这项研究还将进一步机械阐明FGL2中和细胞疗法如何诱导BTRM细胞和我们如何进行额外的改进，将这种疗法转移到下一阶段。最终，这个小说领域将改变GBM的处理。