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

项目总结 尽管嵌合抗原受体(CART)T细胞疗法在治疗B细胞方面的活性令人印象深刻 对于恶性肿瘤，治疗受到细胞因子释放综合征(CRS)和神经毒性的发展的限制， 以及较低的持久响应率。而CRS与细胞因子的极端升高有关 与T细胞增殖相关的神经毒性的确切病因尚不清楚，也没有治疗的选择 神经毒性是可用的。然而，很明显，抑制性髓系细胞和细胞因子 对CART细胞的毒性和抗药性都有贡献。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力。我们的 强有力的临床前数据表明，GM-CSF抑制减少单核细胞激活，增强CART细胞 新型CART异种移植模型的作用及预防CRS和神经毒性的发展 与细胞相关的毒性。我们的进一步研究表明，破坏CART细胞中的GM-CSF可以改善 它们的凋亡，独立于其对髓系细胞的影响。这些发现得到证实，当我们使用 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。在此基础上，CART19术后GM-CSF中和作用的1/2期多中心研究 启动了细胞疗法。我们的中心假设是GM-CSF的耗尽会导致髓系的调节 细胞行为，改善CART细胞激活，减少CART细胞相关毒性，以及 增强它们的功效。我们将利用我们的实验室工具、新的临床前模型和样本 来验证我们的假设。在本项目的目标1中，我们将研究 CART细胞治疗后GM-CSF和单核细胞。在本项目的目标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细胞的毒性和有效性 新的1/2期临床试验中的治疗。完成这些目标将确定对毒性的新见解 和CART细胞的活性，并将开发一种新的策略来防止CART细胞相关的神经毒性和 CRS，潜在地使CART细胞疗法的门诊给药成为可能。

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.