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

我们在这个应用程序中的目标是测试这样一个假设，即中和新发现的免疫抑制 标准护理化疗后胶质母细胞瘤(GBM)中调节性纤维蛋白原样蛋白2(Fgl2)将引发 脑内肿瘤特异性驻留记忆T细胞(bTrm细胞)，它允许免疫清除 中枢神经系统内的胶质瘤和基底膜复发的预防。这一假说是基于 根据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Fgl2 在基底膜组织中高表达(Yanet al，JNCI，2015)，并可将低级别脑瘤转化为基底膜 (Ltha等人，JNCI，2018年)。敲除肿瘤细胞中的Fgl2可完全消除脑部肿瘤的进展 在免疫能力强的小鼠中没有，但在免疫缺陷的小鼠中不存在(严等人，NAT Commun，2019年)。我们未出版的 初步数据显示，通过给予带有膜锚定的T细胞来中和Fgl2 抗Fgl2单链抗体诱导bTrm细胞直接或在颅内后抵抗颅内肿瘤细胞攻击 移植到幼稚的小鼠中(见初步数据部分)；相同的小鼠无法排斥来自 外周组织挑战。 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细胞疗法在大脑中诱导bTrm细胞；目标2：优化T-aFgl2中和细胞 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治疗候选方案--一种Fgl2中和细胞疗法，可能 永久防止肿瘤复发--这是导致GBM患者死亡的关键致命原因。考虑到Fgl2可以 在几乎所有的GBM中都能检测到，大多数都有非常高的水平，这种候选疗法将是重要的。 这项研究还将进一步从机制上阐明Fgl2中和细胞疗法是如何诱导bTrm细胞和 我们如何才能做出进一步的改进，将这种疗法带入下一阶段。归根结底，这个新领域 将改变对GBM的治疗。

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 Our unpublished preliminary data have shown that neutralizing Fgl2 via administering T cells armed with a membrane-anchored anti-Fgl2 scFv induces bTrm cells that reject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