A Mouse Model to Assess Long Term Immunotherapy-related Adverse Effects in Children

近年来，癌症免疫疗法已成为治疗癌症最有效、最持久的疗法。 好几年了。在一些实体肿瘤和血液系统恶性肿瘤中，免疫治疗已成为护理的标准， 加入手术、化疗、放射治疗和靶向治疗等常规治疗的行列。 嵌合抗原受体-T(CAR-T)疗法在治疗儿童白血病方面取得了令人印象深刻的进展 白血病。人们高度期待检查点抑制抗体免疫疗法，如抗PD-1，抗PD-L1， 和抗CTLA4，将在临床试验中在儿童癌症中进行测试(一些第一阶段试验正在进行中)。然而， 与免疫治疗相关的自身免疫不良事件(IRAE)相当严重，超过 在成人临床试验中，50%的患者出现3级和4级器官毒性。一期临床试验报告 在儿童癌症患者中，抗CTLA4抗体(Ipiimumab)提示IRAE的发生率与 成人，尽管观察期太短，无法确定发育缺陷的独特问题 儿科病人。因此，儿科癌症免疫治疗研究面临的主要挑战是(1) 建立小鼠模型以总结IRAE，特别是儿科患者独有的长期IRAE； 用小鼠模型研究IRAE的发病机制(3)寻找新的靶点，在不阻碍IRAE的情况下降低IRAE 抗肿瘤功效。 损伤相关分子模式(DAMP)在调节组织损伤方面发挥着重要作用， 抗原提呈细胞激活和效应器T细胞功能。我们之前的工作表明CD24- Siglec信号通路抑制由潮湿引发的炎症。我们已经建立了一个小鼠模型 这如实地概括了主要器官中已报道的抗CTLA 4和抗CTLA 4中的irAEs PD-1免疫治疗临床试验。在这里，我们建议在小鼠模型中描述长期的IRAE，并且 探讨DAMPS结合蛋白CD24和Siglecs在IRAE发病机制中的作用。

Cancer immunotherapy has emerged as the most potent and durable treatment for cancers in recent years. In some solid tumors and hematological malignancies, immunotherapy has become the standard of care, joining the ranks of conventional treatment such as surgery, chemotherapy, radiation and targeted therapy. Chimeric antigen receptor – T (CAR-T) therapy has made impressive progress in treatment of pediatric leukemia. It is highly anticipated that checkpoint inhibitor antibody immunotherapy, such anti-PD-1, anti-PD-L1, and anti-CTLA4, will be tested in pediatric cancers in clinical trials (some Phase 1 trials are ongoing) . However, the autoimmune adverse events (irAE) associated with the immunotherapy is quite severe, with greater than 50% of patients developing grade 3 and 4 organ toxicity in adult clinical trials. The report on a Phase 1 trial of anti-CTLA4 antibody (Ipilimumab) on pediatric cancer patients suggested similar rate of irAE as observed in adult, although the observation period is too short to identify issues unique for developmental defects unique for pediatric patients. Therefore, the major challenges in research effort for pediatric cancer immunotherapy are (1) establishing mouse models to recapitulate irAE, especially the long term irAE unique for pediatric patients; (2) using mouse models to study the irAE pathogenesis (3) searching new targets to reduce irAE without impeding anti-tumor efficacy. Damage related molecular patterns (DAMPs) play an important role in regulating tissue damages, antigen presenting cells activation and effector T cell functions. Our previous work demonstrated that CD24- Siglec signaling pathway suppresses inflammation triggered by DAMPs. We have established a mouse model that faithfully recapitulates the irAEs in major organs that have been reported in anti-CTLA 4 and anti- PD-1 immunotherapy clinical trials. Here we propose to characterize the long term irAE in mouse model, and to examine the role of DAMPs-binding protein CD24 and Siglecs in irAE pathogenesis.