Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma

被引：228

作者：

Da Via, Matteo C. ^{[1
]}

Dietrich, Oliver ^{[2
]}

Truger, Marietta ^{[3
]}

Arampatzi, Panagiota ^{[4
]}

Duell, Johannes ^{[1
]}

Heidemeier, Anke ^{[5
]}

Zhou, Xiang ^{[1
]}

Danhof, Sophia ^{[1
]}

Kraus, Sabrina ^{[1
]}

Chatterjee, Manik ^{[1
]}

Meggendorfer, Manja ^{[3
]}

Twardziok, Sven ^{[3
]}

Goebeler, Maria-Elisabeth ^{[1
]}

Topp, Max S. ^{[1
]}

Hudecek, Michael ^{[1
]}

Prommersberger, Sabrina ^{[1
]}

Hege, Kristen ^{[6
]}

Kaiser, Shari ^{[6
]}

Fuhr, Viktoria ^{[7
]}

Weinhold, Niels ^{[8
]}

Rosenwald, Andreas ^{[7
]}

Erhard, Florian ^{[9
]}

Haferlach, Claudia ^{[3
]}

Einsele, Hermann ^{[1
]}

Kortuem, K. Martin ^{[1
]}

Saliba, Antoine-Emmanuel ^{[2
]}

Rasche, Leo ^{[1
,10
]}

机构：

[1] Univ Hosp Wurzburg, Dept Internal Med 2, Wurzburg, Germany

[2] Helmholtz Ctr Infect Res, Helmholtz Inst RNA Based Infect Res, Wurzburg, Germany

[3] Munich Leukemia Lab, Munich, Germany

[4] Univ Wurzburg, Core Unit Syst Med, Wurzburg, Germany

[5] Univ Hosp Wurzburg, Dept Radiol, Wurzburg, Germany

[6] Bristol Myers Squibb, San Francisco, CA USA

[7] Univ Wurzburg, Inst Pathol, Wurzburg, Germany

[8] Univ Hosp Heidelberg, Med Klin 5, Heidelberg, Germany

[9] Univ Wurzburg, Inst Virol & Immunobiol, Wurzburg, Germany

[10] Univ Hosp Wurzburg, Mildred Scheel Early Career Ctr, Wurzburg, Germany

来源：

NATURE MEDICINE | 2021年 / 27卷 / 04期

关键词：

D O I：

10.1038/s41591-021-01245-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial (NCT03361748) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.

引用

页码：616 / 619

页数：18

共 28 条

[1] Clinical Activity of REGN1979, a Bispecific Human, Anti-CD20 x Anti-CD3 Antibody, in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL) [J].

Bannerji, Rajat ;

Allan, John N. ;

Arnason, Jon E. ;

Brown, Jennifer R. ;

Advani, Ranjana H. ;

Barnes, Jeffrey A. ;

Ansell, Stephen M. ;

O'Brien, Susan M. ;

Chavez, Julio ;

Duell, Johannes ;

David, Kevin A. ;

Martin, Peter ;

Joyce, Robin M. ;

Charnas, Robert ;

Ambati, Srikanth R. ;

Adriaens, Lieve ;

Ufkin, Melanie ;

Zhu, Min ;

Li, Jingjin ;

Gasparini, Peter ;

Ibrahim, Anfal ;

Jankovic, Vladimir ;

Fiaschi, Nathalie ;

Aina, Olulanu ;

Zhang, Wen ;

Deering, Raquel P. ;

Hamon, Sara ;

Thurston, Gavin ;

Murphy, Andrew J. ;

Weinreich, David M. ;

Yancopoulos, George D. ;

Lowy, Israel ;

Sternberg, David ;

Topp, Max S. .

BLOOD, 2019, 134

[2] T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma [J].

Brudno, Jennifer N. ;

Maric, Irina ;

Hartman, Steven D. ;

Rose, Jeremy J. ;

Wang, Michael ;

Lam, Norris ;

Stetler-Stevenson, Maryalice ;

Salem, Dalia ;

Yuan, Constance ;

Pavletic, Steven ;

Kanakry, Jennifer A. ;

Ali, Syed Abbas ;

Mikkilineni, Lekha ;

Feldman, Steven A. ;

Stroncek, David F. ;

Hansen, Brenna G. ;

Lawrence, Judith ;

Patel, Rashmika ;

Hakim, Frances ;

Gress, Ronald E. ;

Kochenderfer, James N. .

JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (22) :2267-+

[3] Integrating single-cell transcriptomic data across different conditions, technologies, and species [J].

Butler, Andrew ;

Hoffman, Paul ;

Smibert, Peter ;

Papalexi, Efthymia ;

Satija, Rahul .

NATURE BIOTECHNOLOGY, 2018, 36 (05) :411-+

[4] CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma [J].

Casucci, Monica ;

di Robilant, Benedetta Nicolis ;

Falcone, Laura ;

Camisa, Barbara ;

Norelli, Margherita ;

Genovese, Pietro ;

Gentner, Bernhard ;

Gullotta, Fabiana ;

Ponzoni, Maurilio ;

Bernardi, Massimo ;

Marcatti, Magda ;

Saudemont, Aurore ;

Bordignon, Claudio ;

Savoldo, Barbara ;

Ciceri, Fabio ;

Naldini, Luigi ;

Dotti, Gianpietro ;

Bonini, Chiara ;

Bondanza, Attilio .

BLOOD, 2013, 122 (20) :3461-3472

[5] Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications [J].

Chen, Xiaoyu ;

Schulz-Trieglaff, Ole ;

Shaw, Richard ;

Barnes, Bret ;

Schlesinger, Felix ;

Kallberg, Morten ;

Cox, Anthony J. ;

Kruglyakl, Semyon ;

Saunders, Christopher T. .

BIOINFORMATICS, 2016, 32 (08) :1220-1222

[6] Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors [J].

Cheng, Jiqiu ;

Demeulemeester, Jonas ;

Wedge, David C. ;

Vollan, Hans Kristian M. ;

Pitt, Jason J. ;

Russnes, Hege G. ;

Pandey, Bina P. ;

Nilsen, Gro ;

Nord, Silje ;

Bignell, Graham R. ;

White, Kevin P. ;

Borresen-Dale, Anne-Lise ;

Campbell, Peter J. ;

Kristensen, Vessela N. ;

Stratton, Michael R. ;

Lingjrde, Ole Christian ;

Moreau, Yves ;

Van Loo, Peter .

NATURE COMMUNICATIONS, 2017, 8

[7] B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma [J].

Cohen, Adam D. ;

Garfall, Alfred L. ;

Stadtmauer, Edward A. ;

Melenhorst, J. Joseph ;

Lacey, Simon F. ;

Lancaster, Eric ;

Vogl, Dan T. ;

Weiss, Brendan M. ;

Dengel, Karen ;

Nelson, Annemarie ;

Plesa, Gabriela ;

Chen, Fang ;

Davis, Megan M. ;

Hwang, Wei-Ting ;

Young, Regina M. ;

Brogdon, Jennifer L. ;

Isaacs, Randi ;

Pruteanu-Malinici, Iulian ;

Siegel, Don L. ;

Levine, Bruce L. ;

June, Carl H. ;

Milone, Michael C. .

JOURNAL OF CLINICAL INVESTIGATION, 2019, 129 (06) :2210-2221

[8] Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma [J].

de Larrea, Carlos Fernandez ;

Staehr, Mette ;

Lopez, Andrea, V ;

Ng, Khong Y. ;

Chen, Yunxin ;

Godfrey, William D. ;

Purdon, Terence J. ;

Ponomarev, Vladimir ;

Wendel, Hans-Guido ;

Brentjens, Renier J. ;

Smith, Eric L. .

BLOOD CANCER DISCOVERY, 2020, 1 (02) :146-154

[9] Estimating pseudocounts and fold changes for digital expression measurements [J].

Erhard, Florian .

BIOINFORMATICS, 2018, 34 (23) :4054-4063

[10]

Garfall AL, 2019, NATURE, V575, P450, DOI 10.1038/d41586-019-03495-3

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