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

评估儿童长期免疫治疗相关不良反应的小鼠模型

• 批准号: 10231128
• 负责人: Yin Wang
• 金额: $ 41.42万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231128
• 关键词: Adult; Adverse effects; Adverse event; Affect; Age; Antibodies; Antigen-Presenting Cells; Attention; Autoimmune; B-Cell Leukemia; Binding Proteins; CTLA4 gene; Cancer Model; Cancer Patient; Cardiovascular system; Cell Therapy; Cell physiology; Chemotherapy and/or radiation; Child; Childhood; Childhood Leukemia; Clinical Trials; Conduct Clinical Trials; Cytolysis; Data; Defect; Development; Disease; Endocrine system; Hematologic Neoplasms; Human; Immune checkpoint inhibitor; Immune response; Immunotherapeutic agent; Immunotherapy; Inflammation; Investigation; Investigational Therapies; Knock-in; Lead; Life; Link; Long-Term Effects; Malignant Childhood Neoplasm; Mediating; Metastatic Melanoma; Modeling; Molecular; Mus; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Organ; Pathogenesis; Patients; Pattern; Pediatric Oncology; Phase II Clinical Trials; Play; Pre-Clinical Model; Prevention; Protocols documentation; Publications; Radiation therapy; Renal function; Reporting; Reproduction; Research; Role; Serious Adverse Event; Signal Pathway; Solid; Solid Neoplasm; System; T-Lymphocyte; Testing; Therapeutic Effect; Tissues; Toxic effect; Translational Research; Translations; Tumor Immunity; Work; anti-CTLA4; anti-CTLA4 antibodies; anti-PD-1; anti-PD-L1; antibody immunotherapy; autoimmune pathogenesis; cancer immunotherapy; cancer therapy; chimeric antigen receptor; conventional therapy; cytotoxicity; effector T cell; frontier; genetic approach; immune-related adverse events; immunotherapy clinical trials; in vivo; industry partner; innovation; ipilimumab; liver function; mouse model; novel; pediatric patients; phase I trial; prevent; response; screening; sialic acid binding Ig-like lectin; side effect; standard of care; targeted treatment; tissue injury; tool; tumor

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.

近年来，癌症免疫疗法已成为癌症最有效和最持久的治疗方法。 年在一些实体瘤和血液恶性肿瘤中，免疫疗法已成为护理标准， 加入传统治疗的行列，如手术、化疗、放疗和靶向治疗。 嵌合抗原受体- T（CAR-T）疗法在治疗儿童肿瘤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剂抗体免疫疗法，如抗PD-1，抗PD-L1， 和抗CTLA 4，将在临床试验中在儿科癌症中进行测试（一些I期试验正在进行中）。然而，在这方面， 与免疫治疗相关的自身免疫不良事件（irAE）是相当严重的， 在成人临床试验中，50%的患者发生3级和4级器官毒性。一项1期试验的报告， 抗CTLA 4抗体（Ipilimumab）在儿科癌症患者中的应用表明，irAE的发生率与 成年人，虽然观察期太短，无法确定发育缺陷的独特问题， 儿科患者。因此，儿科癌症免疫治疗研究工作的主要挑战是（1） 建立再现irAE的小鼠模型，特别是儿科患者特有的长期irAE;（2） 利用小鼠模型研究irAE的发病机制（3）寻找新的靶点，减少irAE，而不阻碍 抗肿瘤功效。 损伤相关分子模式（DAMP）在调节组织损伤中起重要作用， 抗原呈递细胞活化和效应T细胞功能。我们以前的工作表明，CD 24- Siglec信号通路抑制由DAMP触发的炎症。我们建立了一个小鼠模型 这忠实地概括了在抗CTLA 4和抗CTLA 4中报告的主要器官中的irAE， PD-1免疫治疗临床试验。在这里，我们建议在小鼠模型中表征长期irAE， 研究DAMPs结合蛋白CD 24和Siglecs在irAE发病机制中的作用。