美国斯坦福大学医学院Ansuman T. Satpathy和宾夕法尼亚大学Denis Migliorini研究组合作取得最新进展。他们发现单细胞分析鉴定表达CD19的脑壁细胞可作为嵌合抗原受体（CAR）T免疫疗法的潜在非肿瘤靶标。该项研究成果发表在2020年9月21日的《细胞》上。
他们报告说，围绕内皮细胞并且对血脑屏障完整性至关重要的壁细胞表达CD19。他们使用单细胞RNA测序数据鉴定脑壁细胞中的CD19表达，并在蛋白水平确认血管周围染色。脑中CD19的表达与壁细胞谱系一起发生在发育的早期，并在整个成年期，持续存在于整个脑区域。
小鼠壁细胞显示出较低水平的Cd19表达，表明在临床前动物模型中存在神经毒性。这些数据提示了CD19定向疗法中神经毒性的靶向机制，并突出了人单细胞图谱在设计免疫疗法中的实用性。
据悉，CD19定向免疫疗法在临床上可有效治疗B细胞恶性肿瘤，但也引起神经毒性的高发。接受细胞或双特异性T细胞接合剂（BiTE）抗体治疗的患者亚群显示出严重的神经毒性，包括与T细胞浸入大脑相关的致命性脑水肿。
附：英文原文
Title: Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies
Author: Kevin R. Parker, Denis Migliorini, Eric Perkey, Kathryn E. Yost, Aparna Bhaduri, Puneet Bagga, Mohammad Haris, Neil E. Wilson, Fang Liu, Khatuna Gabunia, John Scholler, Thomas J. Montine, Vijay G. Bhoj, Ravinder Reddy, Suyash Mohan, Ivan Maillard, Arnold R. Kriegstein, Carl H. June, Howard Y. Chang, Avery D. Posey, Ansuman T. Satpathy
Issue&Volume: 2020-09-21
Abstract: CD19-directed immunotherapies are clinically effective for treating B cell malignanciesbut also cause a high incidence of neurotoxicity. A subset of patients treated withchimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodiesdisplay severe neurotoxicity, including fatal cerebral edema associated with T cellinfiltration into the brain. Here, we report that mural cells, which surround theendothelium and are critical for blood-brain-barrier integrity, express CD19. We identifyCD19 expression in brain mural cells using single-cell RNA sequencing data and confirmperivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of muralcell lineages and persists throughout adulthood across brain regions. Mouse muralcells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity.These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapiesand highlight the utility of human single-cell atlases for designing immunotherapies.
DOI: 10.1016/j.cell.2020.08.022
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31013-8