The IL-18-IFNγ axis predicts response to immunotherapy

IL-18-IFNγ轴预测对免疫治疗的反应

• 批准号: 10584972
• 负责人: HEATHER LEIGH HERD GUSTAFSON
• 金额: $ 84.58万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584972
• 关键词: Adopted; Antigens; Antitumor Response; Automobile Driving; Biological Markers; Biology; Blood; Body Weight decreased; CD14 gene; CD19 gene; CD22 gene; Cell physiology; Cell-Mediated Cytolysis; Cells; Cellular immunotherapy; Cessation of life; Characteristics; Child; Childhood; Childhood Hematopoietic Neoplasm; Childhood Leukemia; Clinical; Clinical Trials; Collaborations; Coupled; Cytokine Signaling; Dangerousness; Data; Development; Disease; Dose; Engineering; Engraftment; Etiology; Excision; Functional disorder; Genetic Predisposition to Disease; Genetic Transcription; Grant; HIF1A gene; Hematopoietic Neoplasms; Hemophagocytic Lymphohistiocytoses; Histology; Human; IL18 gene; Immune; Immune system; Immunity; Immunotherapy; In Vitro; Individual; Inflammatory; Interferon Type II; Interferons; Interleukin-10; Interleukin-12; Investments; KLRB1 gene; Kinetics; Life; Machine Learning; Measures; Mediating; Medical; Myelogenous; Myeloproliferative disease; Nervous System Trauma; Neuroblastoma; Outcome; Patients; Pediatric Neoplasm; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Production; Recording of previous events; Recurrence; Relapse; Research; Resources; Risk; Role; Safety; Sampling; Series; Serum; Signal Transduction; Solid Neoplasm; T-Lymphocyte; The Jackson Laboratory; Therapeutic; Time; Toxic effect; Treatment-related toxicity; Tumor Biology; Work; biomarker validation; blood treatment; blood-brain barrier crossing; chimeric antigen receptor; chimeric antigen receptor T cells; clinical biomarkers; clinical predictors; cohort; cytokine; cytokine release syndrome; experience; experimental study; familial hemophagocytic lymphohistiocytosis; humanized mouse; improved; improved outcome; insight; interleukin-18 receptor; leukemia; machine learning algorithm; monocyte; mouse model; neurotoxicity; novel; patient population; patient response; patient subsets; pediatric patients; predicting response; predictive marker; programs; response; side effect; success; survival prediction; trafficking; trend; trial design; tumor

ABSTRACT CAR T-cells have revolutionized the treatment of pediatric leukemia. However, ~50% of responsive patients eventually relapse and in ~50-70% of patients, this therapy induces devastating side effects (i.e. neurotoxicity (NTX) and cytokine release syndrome (CRS)), potentially leading to long term neurological damage and death. There are no clinical biomarkers to predict survival or toxicity despite a crucial need. SCRI has made a substantial investment in CAR T therapy and is a world leader in pediatric CAR T cell clinical trials. This proposed project will build upon this program by helping to predict and mitigate the devastating, life-threatening side effects caused by this revolutionary therapy and may aide in the prediction of non-response cases. Data from our pilot experiments utilizing samples from patients on CAR-T trials at SCRI suggests that pre-monocyte activation status and cytokine profiles from the monocyte fraction of a patient can predict CAR T toxicity across both blood and solid tumors, in particular we see trends in the IL-18- IFN𝛾𝛾 axis. We plan to act on this encouraging pilot data in this proposal to develop a series of validated monocytic biomarkers (cytokine, flow and transcriptional) and machine learning algorithms which can be utilized prior to patients going on trial in order to save time and resources for patients who are set to fail treatment and allow medical teams to be more prepared to mitigate toxicity in those who are more prone to it. The proposal further expands to the development a humanized mouse model that can adopt the healthy donor and pediatric patient immune systems recapturing natural variability in human immunity to investigate causality of the IL-18- IFN𝛾𝛾 axis in driving both therapeutic toxicity. The project combines existing but unused large bank of SCRI CAR T patient samples/data with monocytic omics profiling to develop predictive biomarkers for therapeutic toxicity (AIM 1). We aim to further extend the impact of this work to mechanistically understand why certain patients’ cells are working against them through the use of novel humanized mouse models (AIM2). This is built upon to develop therapeutics or strategies to improve safety and efficacy of CAR-T treatments. Importantly, our team of experts in clinical CAR T (Dr. Rebecca Gardner, Dr. Navin Pinto), machine learning (Dr. Bobbie-Jo Webb-Robertson), humanized mice (Dr. James Keck), and myeloid tumor biology (Dr. Heather Gustafson) pose this grant for optimal success.

抽象的 汽车T细胞彻底改变了对小儿白血病的治疗。但是，约有50％的反应敏感患者 这种疗法均匀地继电器和约50-70％的患者，会引起毁灭性的副作用（即神经毒性 （NTX）和细胞因子释放综合征（CRS）），可能导致长期神经系统损害和死亡。 没有临床生物标志物可以预测至关重要的生存或毒性目的地。 SCRI做出了实质性的 对汽车治疗的投资，是小儿CAR T细胞临床试验的世界领导者。这个建议的项目 将通过帮助预测和减轻造成的破坏性，威胁生命的副作用来建立该计划 通过这种革命性的疗法，并可能有助于预测无响应病例。来自我们的飞行员的数据 使用SCRI的CAR-T试验中患者的样本的实验表明，前单细胞激活 来自患者单核细胞分数的状态和细胞因子谱可以预测两种血液中的CAR T毒性 和实体瘤，尤其是我们看到IL-18- IFN𝛾𝛾轴的趋势。我们计划采取这种令人鼓舞的飞行员的行动 此提案中的数据，以开发一系列经过验证的单核细胞生物标志物（细胞因子，流量和转录） 和机器学习算法，可以在患者进行审判之前使用，以节省时间和 为了使治疗失败并允许医疗团队的患者提供更多的准备以减轻治疗的患者 那些更容易容易出现的人的毒性。该提案进一步扩展到人性化的老鼠的发展 可以采用健康的供体和儿科患者免疫系统的模型，从而重新获得自然变异性 人类免疫能够研究IL-18-轴的卡路，以驱动两种治疗性毒性。项目 将现有但未使用的大型SCRI CAR T患者样品/数据与单核细胞映射分析结合在一起 开发用于治疗毒性的预测生物标志物（AIM 1）。我们的目标是进一步扩大这项工作的影响 为了机械理解为什么某些患者的细胞通过使用新颖 人源化小鼠模型（AIM2）。这是基于制定治疗或提高安全和策略的基础 CAR-T治疗的有效性。重要的是，我们的临床汽车专家团队（Rebecca Gardner博士，Navin博士 Pinto），机器学习（Bobbie-Jo Webb-Robertson博士），人源化老鼠（James Keck博士）和髓样 肿瘤生物学（Heather Gustafson博士）为最佳成功提供了这笔赠款。