Single-cell antigen-specific landscape of CART infusion product identifies determinants of CD19-positive relapse in patients with ALL

被引：121

作者：

Bai, Zhiliang ^{[1
]}

Woodhouse, Steven ^{[2
,3
]}

Zhao, Ziran ^{[4
,5
,6
,7
]}

Arya, Rahul ^{[8
,9
]}

Govek, Kiya ^{[2
,3
]}

Kim, Dongjoo ^{[1
]}

Lundh, Stefan ^{[5
]}

Baysoy, Alev ^{[1
]}

Sun, Hongxing ^{[4
]}

Deng, Yanxiang ^{[1
]}

Xiao, Yang ^{[1
]}

Barrett, David M. ^{[8
,9
]}

Myers, Regina M. ^{[8
]}

Grupp, Stephan A. ^{[8
,9
]}

June, Carl H. ^{[4
,5
,6
]}

Fan, Rong ^{[1
,10
,11
,12
]}

Camara, Pablo G. ^{[2
,3
]}

Melenhorst, J. Joseph ^{[4
,5
,6
,7
]}

机构：

[1] Yale Univ, Dept Biomed Engn, New Haven, CT 06520 USA

[2] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA

[3] Univ Penn, Inst Biomed Informat, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Ctr Cellular Immunotherapies, Perelman Sch Med, Philadelphia, PA 19104 USA

[6] Univ Penn, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

[7] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA

[8] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[9] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[10] Yale Sch Med, Yale Stem Cell Ctr, New Haven, CT 06520 USA

[11] Yale Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA

[12] Yale Sch Med, Human & Translat Immunol, New Haven, CT 06520 USA

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 23期

关键词：

T-CELLS; B-CELL; TECHNOLOGIES; RESISTANCE; CHILDREN;

D O I：

10.1126/sciadv.abj2820

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

A notable number of acute lymphoblastic leukemia (ALL) patients develop CD19-positive relapse within 1 year after receiving chimeric antigen receptor (CAR) T cell therapy. It remains unclear if the long-term response is associated with the characteristics of CART cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes. Here, we present 101,326 single-cell transcriptomes and surface protein landscape from the infusion products of 12 ALL patients. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of T helper 2 function was associated with CD19-positive relapse compared with durable responders (remission, >54 months). Proteomic data revealed that the frequency of early memory T cells, rather than activation or coinhibitory signatures, could distinguish the relapse. These findings were corroborated by independent functional profiling of 49 patients, and an integrative model was developed to predict the response. Our data unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long-term remission.

引用

页数：16

共 48 条

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