Towards Safer and More Effective CART Cell Therapy Through the Modulation of Myeloid Cytokines

通过调节骨髓细胞因子实现更安全、更有效的 CART 细胞疗法

基本信息

批准号：
10340529
负责人：
Saad J. Kenderian
金额：
$ 60.63万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-09 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340529
关键词：
Acute Lymphocytic Leukemia Affect Apoptosis Apoptotic B lymphoid malignancy B-Cell Lymphomas Blood specimen CAR T cell therapy CD19 gene COVID-19 COVID-19 patient Cell Death Cell Therapy Cell physiology Cells Clinical Clinical Trials Data Development Etiology Functional disorder Funding Goals Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Hematopoietic Impairment In Vitro Interleukin 6 Receptor Interruption Knock-out Laboratories Life Mediating Mediator of activation protein Multi-Institutional Clinical Trial Multicenter Studies Myelogenous Myeloid Cells Outcome Outpatients Pathway interactions Patients Phase Phase I/II Clinical Trial Pre-Clinical Model Prevention Publishing Receptor Cell Refractory Relapse Resistance Resolution Role Sampling Severities Site T-Lymphocyte Testing Therapeutic Toxic effect United States Work Xenograft Model base cancer therapy cell behavior chimeric antigen receptor cohort cytokine cytokine release syndrome first-in-human improved in vivo insight laboratory experiment large cell Diffuse non-Hodgkin&apos s lymphoma monocyte neurotoxicity neutralizing antibody novel novel strategies post-COVID-19 pre-clinical prevent receptor response severe COVID-19 tocilizumab tool transcription activator-like effector nucleases tumor

项目摘要

PROJECT SUMMARY Despite the impressive activity of chimeric antigen receptor (CART) T cell therapy in the treatment of B-cell malignancies, the therapy is limited by the development of cytokine release syndrome (CRS) and neurotoxicity, as well as by lower rates of durable responses. While CRS is related to extreme elevation of cytokines associated with T cell expansion, the exact etiology of neurotoxicity is unknown and no options for treatment of neurotoxicity are available. It has, however, become apparent that inhibitory myeloid cells and cytokines contribute to both CART cell toxicities and resistance. We have identified granulocyte-macrophage colony- stimulating factor (GM-CSF) as a dominant driver for CART cell toxicity and inhibition of their functions. Our robust preclinical data indicate that GM-CSF inhibition reduces monocyte activation, enhances CART cell functions and prevents the development of both CRS and neurotoxicity in a novel xenograft model for CART cell-associated toxicities. Our additional studies suggest that GM-CSF disruption in CART cells ameliorates their apoptosis, independent of its effect on myeloid cells. These findings were corroborated when we utilized GM-CSF depletion as a therapeutic strategy in patients with cytokine storm and severe Coronavirus Disease 2019, COVID-19. Based on this work, a Phase 1/2 multi-center study of GM-CSF neutralization after CART19 cell therapy was launched. Our central hypothesis is that depletion of GM-CSF results in modulation of myeloid cell behavior, amelioration of CART cell activation, reduction of CART cell associated toxicities, and enhancement of their efficacy. We will leverage our laboratory tools, novel preclinical models, and samples from this clinical trial to test our hypothesis. In Aim 1 of this project, we will examine the interactions between GM-CSF and monocytes after CART cell therapy. In Aim 2 of this project, we will study the effect of GM-CSF directly on CART cells, and Aim 3 will test how these changes affect toxicity and efficacy of CART19 cell therapy in the novel Phase 1/2 clinical trial. Completion of these Aims will identify novel insights into the toxicity and activity of CART cells and will develop a new strategy to prevent CART cell associated neurotoxicity and CRS, potentially enabling the outpatient administration of CART cell therapy.

项目概要尽管嵌合抗原受体 (CART) T 细胞疗法在治疗 B 细胞方面具有令人印象深刻的活性恶性肿瘤，该疗法受到细胞因子释放综合征（CRS）和神经毒性的发展的限制，以及持久反应率较低。而CRS与细胞因子的极度升高有关与 T 细胞扩增有关，神经毒性的确切病因尚不清楚，并且没有治疗选择存在神经毒性。然而，很明显，抑制性骨髓细胞和细胞因子有助于 CART 细胞毒性和耐药性。我们已经鉴定出粒细胞-巨噬细胞集落- 刺激因子（GM-CSF）是 CART 细胞毒性和功能抑制的主要驱动因素。我们的可靠的临床前数据表明，GM-CSF 抑制可减少单核细胞活化，增强 CART 细胞在新型 CART 异种移植模型中发挥作用并防止 CRS 和神经毒性的发展细胞相关的毒性。我们的其他研究表明，CART 细胞中的 GM-CSF 破坏可改善它们的凋亡，与其对骨髓细胞的影响无关。当我们使用时，这些发现得到了证实 GM-CSF耗竭作为细胞因子风暴和严重冠状病毒病患者的治疗策略 2019 年，新冠肺炎 (COVID-19)。基于这项工作，CART19后GM-CSF中和的1/2期多中心研究推出细胞疗法。我们的中心假设是 GM-CSF 的消耗会导致骨髓细胞的调节细胞行为、改善 CART 细胞活化、减少 CART 细胞相关毒性，以及增强其功效。我们将利用我们的实验室工具、新颖的临床前模型和样本从这个临床试验来检验我们的假设。在本项目的目标 1 中，我们将研究之间的相互作用 CART 细胞治疗后的 GM-CSF 和单核细胞。在该项目的目标2中，我们将研究GM-CSF的作用直接作用于CART细胞，Aim 3将测试这些变化如何影响CART19细胞的毒性和功效新型 1/2 期临床试验中的治疗。完成这些目标将对毒性产生新的见解和 CART 细胞的活性，并将开发一种新策略来预防 CART 细胞相关的神经毒性和 CRS，有可能使 CART 细胞疗法的门诊给药成为可能。