CD19 CAR T细胞治疗后持续的细胞减少与克隆扩增的IFNγ表达CD8 T细胞浸润骨髓有关。
Prolonged cytopenia following CD19 CAR T cell therapy is linked with bone marrow infiltration of clonally expanded IFNγ-expressing CD8 T cells.
发表日期：2023 Aug 15
作者：
Paolo Strati, Xubin Li, Qing Deng, Mario L Marques-Piubelli, Jared Henderson, Grace Watson, Laurel Deaton, Taylor Cain, Haopeng Yang, Vida Ravanmehr, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Frederick B Hagemeister, Edwin R Parra, Neeraj Saini, Koichi Takahashi, Nathan H Fowler, Jason R Westin, Raphael E Steiner, Ranjit Nair, Christopher R Flowers, Linghua Wang, Sairah Ahmed, Gheath Al-Atrash, Francisco Vega, Sattva S Neelapu, Michael R Green
来源：
Stem Cell Research & Therapy
摘要：
自体抗CD19嵌合抗原受体T细胞（CAR T）疗法在复发/难治性大B细胞淋巴瘤（rrLBCL）中具有高度有效性，但与延迟康复的毒性有关。虽然白细胞介素释放综合征和神经毒性的生物学机制得到了研究，但对于持续细胞减少（定义为CAR T输注后持续30天以上的≥3级细胞减少）的病理生理机制了解不足。我们对健康供体和rrLBCL患者的骨髓样本进行了单细胞RNA测序，并发现出现明显增加的克隆扩增的CX3CR1高表达细胞毒性T细胞频率，这些细胞表达高水平的干扰素（IFN）-γ和细胞因子信号通路基因集，与持续细胞减少相关。与此一致，我们发现这些患者的造血干细胞表达IFN-γ响应标志。IFN-γ破坏了造血干细胞的自我更新和分化能力，并可通过血小板生成素激动剂或IFN-γ中和抗体进行靶向治疗，突出了一种潜在的基于机制的治疗CAR T相关持续细胞减少的方法。版权所有 ©2023 作者。由Elsevier Inc.发表并保留所有权利。
Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.