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

我们在本申请中的目标是测试中和新鉴定的免疫抑制性抗体的假设。 胶质母细胞瘤（GBM）标准治疗化疗后的调节纤维蛋白原样蛋白2（Fgl 2）将触发 脑中的肿瘤特异性驻留记忆T细胞（bTrm细胞），其允许免疫清除 中枢神经系统胶质瘤和GBM复发的预防。这个假设是基于 我们最近发表的论文和新建立的初步数据。简而言之，我们发现Fgl 2 在GBM组织中高度表达（Yan et al，JNCI，2015），可将低级别脑肿瘤转化为GBM （Latha等人，JNCI，2018）。敲除肿瘤细胞中的Fgl 2完全消除了大脑中的肿瘤进展 免疫活性小鼠中，但免疫缺陷小鼠中没有（Yan et al，Nat Commun，2019）。我们未发表 初步数据显示，通过给予装备有膜锚定的T细胞来中和Fg 12， 抗Fgl 2 scFv诱导bTrm细胞直接或在颅内肿瘤细胞攻击后拒绝颅内肿瘤细胞攻击 移植到幼稚小鼠中（参见初步数据部分）;相同的小鼠不能排斥来自 外周组织激发。 为了检验我们的中心假设，提出了以下目标：目标1：确定T-aFgl 2- 中和T细胞疗法诱导脑中的bTrm细胞;目的2：优化T-aFgl 2-中和细胞 本发明的目的是开发新一代T-aFgl 2细胞疗法，以提高安全性和治疗功效。 影响：这项研究将产生一种治疗候选物-Fgl 2中和细胞疗法， 永久防止肿瘤复发-GBM患者死亡的关键致命原因。考虑到Fgl 2可以 在几乎所有的GBM中检测到，大多数具有非常高的水平，这种候选治疗将是重要的。 该研究还将进一步从机制上阐明Fgl 2中和细胞疗法如何诱导bTrm细胞和 我们如何能做出进一步的改进，使这种治疗进入下一阶段。最终，这个新领域 将改变GBM的治疗方式

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 Our unpublished preliminary data have shown that neutralizing Fgl2 via administering T cells armed with a membrane-anchored anti-Fgl2 scFv induces bTrm cells that reject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.