Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
06
05
2021
accepted:
28
09
2021
pubmed:
12
12
2021
medline:
22
2
2022
entrez:
11
12
2021
Statut:
ppublish
Résumé
B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial ( NCT03548207 ) and who developed a progressive movement disorder with features of parkinsonism approximately 3 months after ciltacabtagene autoleucel BCMA-targeted CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We show BCMA expression on neurons and astrocytes in the patient's basal ganglia. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting that this might be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade 3 or higher parkinsonism on the phase 2 ciltacabtagene autoleucel trial and of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.
Identifiants
pubmed: 34893771
doi: 10.1038/s41591-021-01564-7
pii: 10.1038/s41591-021-01564-7
pmc: PMC8678323
mid: NIHMS1750428
doi:
Substances chimiques
B-Cell Maturation Antigen
0
Receptors, Chimeric Antigen
0
Banques de données
ClinicalTrials.gov
['NCT03548207']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2099-2103Subventions
Organisme : NCI NIH HHS
ID : R01 CA244899
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA252222
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Kumar, S. K. et al. Multiple myeloma. Nat. Rev. Dis. Prim. 3, 17046 (2017).
doi: 10.1038/nrdp.2017.46
Madduri, D., Dhodapkar, M. V., Lonial, S., Jagannath, S. & Cho, H. J. SOHO state of the art updates and next questions: T-cell-directed immune therapies for multiple myeloma: chimeric antigen receptor-modified T cells and bispecific T-cell-engaging agents. Clin. Lymphoma Myeloma Leuk. 19, 537–544 (2019).
doi: 10.1016/j.clml.2019.08.002
Shah, N., Chari, A., Scott, E., Mezzi, K. & Usmani, S. Z. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 34, 985–1005 (2020).
Shah, U. A. & Mailankody, S. Emerging immunotherapies in multiple myeloma. Brit. Med. J. 370, m3176 (2020).
doi: 10.1136/bmj.m3176
Bu, D. X. et al. Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma. Oncotarget 9, 25764–25780 (2018).
doi: 10.18632/oncotarget.25359
Carpenter, R. O. et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048–2060 (2013).
doi: 10.1158/1078-0432.CCR-12-2422
Khattar, P. et al. B-cell maturation antigen is exclusively expressed in a wide range of B-cell and plasma cell neoplasm and in a potential therapeutic target for BCMA directed therapies. Blood 130, 2755–2755 (2017).
Sanchez, E. et al. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br. J. Haematol. 158, 727–738 (2012).
doi: 10.1111/j.1365-2141.2012.09241.x
Sanchez, E. et al. Soluble B-cell maturation antigen mediates tumor-induced immune deficiency in multiple myeloma. Clin. Cancer Res. 22, 3383–3397 (2016).
doi: 10.1158/1078-0432.CCR-15-2224
Tai, Y. T. et al. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 127, 3225–3236 (2016).
doi: 10.1182/blood-2016-01-691162
Munshi, N. C. et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384, 705–716 (2021).
doi: 10.1056/NEJMoa2024850
Raje, N. et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl. J. Med. 380, 1726–1737 (2019).
doi: 10.1056/NEJMoa1817226
Berdeja, J. G. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398, 314–324 (2021).
doi: 10.1016/S0140-6736(21)00933-8
Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transpl. 25, 625–638 (2019).
doi: 10.1016/j.bbmt.2018.12.758
Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).
doi: 10.1038/nrclinonc.2017.148
Gagelmann, N., Ayuk, F., Atanackovic, D. & Kroger, N. B cell maturation antigen-specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: a meta-analysis. Eur. J. Haematol. 104, 318–327 (2020).
doi: 10.1111/ejh.13380
Jatiani, S. S. et al. Myeloma CAR-T CRS management with IL-1R antagonist anakinra. Clin. Lymphoma Myeloma Leuk. 20, 632–636 (2020).
doi: 10.1016/j.clml.2020.04.020
Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489, 391–399 (2012).
doi: 10.1038/nature11405
Lee, L. et al. Evaluation of B cell maturation antigen as a target for antibody drug conjugate mediated cytotoxicity in multiple myeloma. Br. J. Haematol. 174, 911–922 (2016).
doi: 10.1111/bjh.14145
Shah, U. A. & Mailankody, S. CAR T and CAR NK cells in multiple myeloma: expanding the targets. Best Pract. Res. Clin. Haematol. 33, 101141 (2020).
Kotecha, N., Krutzik, P. O. & Irish, J. M. Web-based analysis and publication of flow cytometry experiments. Curr. Protoc. Cytom. Chapter 10, Unit10.17 (2010).
Kolde, R. pheatmap: Pretty Heatmaps. Version 1.0.12. https://rdrr.io/cran/pheatmap/ (2019).
Wickham, H. ggplot2: Elegant Graphics for Data Analysis, (Springer-Verlag, 2016).
Zunder, E. R. et al. Palladium-based mass tag cell barcoding with a doublet-filtering scheme and single-cell deconvolution algorithm. Nat. Protoc. 10, 316–333 (2015).
doi: 10.1038/nprot.2015.020
Nowicka, M. et al. CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets. F1000Res 6, 748 (2017).
doi: 10.12688/f1000research.11622.1
Weber, L. M. diffcyt: Differential discovery in high-dimensional cytometry via high-resolution clustering. Commun. Biol. 2, 183 (2019).
Crowell, H. L., Zanotelli, V. R. T., Chevrier, S. & Robinson, M. D. CATALYST: Cytometry dATa anALYSis Tools. https://github.com/HelenaLC/CATALYST (2020).
Ellis, B. et al. flowCore: basic structures for flow cytometry data. https://www.bioconductor.org/packages/devel/bioc/manuals/flowCore/man/flowCore.pdf (2019).
Van Gassen, S. et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A 87, 636–645 (2015).
doi: 10.1002/cyto.a.22625
Kim, H. J., Lin, Y., Geddes, T. A., Yang, J. Y. H. & Yang, P. CiteFuse enables multi-modal analysis of CITE-seq data. Bioinformatics 36, 4137–4143 (2020).
Amezquita, R. A. et al. Orchestrating single-cell analysis with Bioconductor. Nat. Methods 17, 137–145 (2019).