Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma

被引：9

作者：

Rade, Michael ^{[1
]}

Grieb, Nora ^{[2
,3
]}

Weiss, Ronald ^{[1
,4
]}

Sia, Jaren ^{[5
]}

Fischer, Luise ^{[2
]}

Born, Patrick ^{[2
]}

Boldt, Andreas ^{[4
]}

Fricke, Stephan ^{[4
]}

Franz, Paul ^{[4
]}

Scolnick, Jonathan ^{[5
]}

Venkatraman, Lakshmi ^{[5
]}

Xu, Stacy ^{[5
]}

Kloetzer, Christina ^{[2
]}

Heyn, Simone ^{[2
]}

Kubasch, Anne Sophie ^{[2
]}

Baber, Ronny ^{[6
,7
]}

Wang, Song Yau ^{[2
]}

Bach, Enrica ^{[2
]}

Hoffmann, Sandra ^{[2
]}

Ussmann, Jule ^{[2
]}

Schetschorke, Birthe ^{[2
]}

Hell, Saskia ^{[2
]}

Schwind, Sebastian ^{[2
]}

Metzeler, Klaus H. ^{[2
]}

Herling, Marco ^{[2
]}

Jentzsch, Madlen ^{[2
]}

Franke, Georg-Nikolaus ^{[2
]}

Sack, Ulrich ^{[4
]}

Koehl, Ulrike ^{[1
,4
]}

Platzbecker, Uwe ^{[2
]}

Reiche, Kristin ^{[1
,4
,8
]}

Vucinic, Vladan ^{[2
]}

Merz, Maximilian ^{[2
]}

机构：

[1] Fraunhofer Inst Cell Therapy & Immunol IZI, Leipzig, Germany

[2] Univ Hosp Leipzig, Dept Hematol Cellular Therapy & Hemostaseol, Leipzig, Germany

[3] Univ Hosp Leipzig, Innovat Ctr Comp Assisted Surg, Leipzig, Germany

[4] Univ Hosp Leipzig, Inst Clin Immunol, Leipzig, Germany

[5] Singleron Biotechnol, Cologne, Germany

[6] Univ Hosp Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany

[7] Univ Leipzig, Leipzig Med Biobank, Leipzig, Germany

[8] Ctr Scalable Data Analyt & Artificial Intelligence, Leipzig, Germany

来源：

NATURE CANCER | 2024年 / 5卷 / 09期

关键词：

THERAPY;

D O I：

10.1038/s43018-024-00763-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma. Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.

引用

页码：1318 / 1333

页数：29

共 50 条

[21] Multimodal dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin's lymphoma
Gottschlich, A.
Gruenmeier, R.
Kavaka, V
Mueller, P. J.
Jobst, J.
Thomas, M.
Igl, V
Briukhovetska, D.
Simnica, D.
Lorenzini, T.
Maerkl, F.
Oener, A.
Brabenec, R.
Nandi, S.
Carlini, E.
Tsiverioti, C.
Stock, S.
Michaelides, S.
Jeremias, I
Rosenwald, A.
Marr, C.
Beltran, E.
Endres, S.
Kobold, S.
ONCOLOGY RESEARCH AND TREATMENT, 2023, 46 : 102 - 102
[22] Chimeric antigen receptor T cell therapy for multiple myeloma
Hasegawa, Kana
Hosen, Naoki
INFLAMMATION AND REGENERATION, 2019, 39 (1)
[23] Chimeric antigen receptor T cell therapies for multiple myeloma
Chao Wu
Lina Zhang
Qierra R. Brockman
Fenghuang Zhan
Lijuan Chen
Journal of Hematology & Oncology, 12
[24] PHASE I, OPEN-LABEL TRIAL OF ANTI-BCMA CHIMERIC ANTIGEN RECEPTOR T CELLS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
Zhang, W.
Zhao, W.
Liu, J.
He, A.
Chen, Y.
Cao, X.
Yang, N.
Wang, B.
Zhang, P.
Zhang, Y.
Wang, F.
Lei, B.
Gu, L.
Yang, Y.
Bai, J.
Zhang, R.
Wang, X.
Ma, X.
Wang, J.
Wang, J.
Wei, L.
Zhang, J.
Zang, X.
Zhuang, Q.
Fan, F. X.
HAEMATOLOGICA, 2017, 102 : 2 - 3
[25] Effective Treatment of Relapsed/Refractory Multiple Myeloma Including Extramedullary Involvement By BCMA-Specific Chimeric Antigen Receptor-Modified T Cells
Mi, Jian-Qing
Fan, Xiaohu
Xu, Jie
Liu, Yuanfang
Zhuang, Yan
Yang, Shuangshuang
Zhang, Wu
Chen, Bing
Wang, Yueying
Weng, Xiangqin
Li, Junmin
Fu, Weijun
Jiang, Hua
Zhu, Li
Chen, Zhu
Chen, Sai-Juan
Hou, Jian
BLOOD, 2017, 130
[26] Treatment of relapsed or refractory multiple myeloma with bb2121 chimeric antigen receptor T cells
Stocker, Nicolas
HEMATOLOGIE, 2021, 27 (02): : 46 - 47
[27] Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma
Huang, He
uW, Heng-wei
Hu, Yong-xian
JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B, 2020, 21 (01): : 29 - 41
[28] Cardiovascular events during treatment with anti-BCMA chimeric antigen receptor T-cells in multiple myeloma
Mathilde, Chanut
HEMATOLOGIE, 2023, 29 (05): : 274 - 275
[29] Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM)
Cohen, Adam D.
Garfall, Alfred L.
Stadtmauer, Edward A.
Lacey, Simon F.
Lancaster, Eric
Vogl, Dan T.
Weiss, Brendan M.
Ambrose, David E.
Nelson, Anne Marie
Chen, Fang
Plesa, Gabriela
Kulikovskaya, Irina
Gonzalez, Vanessa
Gupta, Minnal
Young, Regina M.
Dengel, Karen
O'keefe, Laura
Le, Samantha
Richardson, Celeste
Isaacs, Randi E.
Melenhorst, J. Joseph
Levine, Bruce L.
June, Carl H.
Milone, Michael C.
BLOOD, 2017, 130
[30] Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-cell Product, in Patients with Relapsed/Refractory Multiple Myeloma
Hu, Hongxiang
Li, Yan
Piasecki, Julia
Hosseyni, Daniela
Yan, Zhicheng
Liu, Xianghong
Ogasawara, Ken
Zhou, Simon
Cheng, Yiming
CLINICAL CANCER RESEARCH, 2025, 31 (06) : 1163 - 1171

← 1 2 3 4 5 →