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Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy

Abstract

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.

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Fig. 1: Persistence of CAR-T cells with an activated effector memory phenotype in the peripheral blood.
Fig. 2: BCMA is expressed in the caudate nucleus of healthy donors and postmortem in the patient after CAR-T cell therapy.

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Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the Icahn School of Medicine at Mount Sinai and Mount Sinai Hospital to determine if the request is subject to any confidentiality and data protection obligations. Requests for data should be addressed to the corresponding author via e-mail, and a reply will be sent within ten business days. Any data and materials that can be shared will be released via a material transfer agreement. Raw and analyzed CITE-seq data are available through the National Center for Biotechnology Information’s Gene Expression Omnibus (accession no. GSE182527). Mass cytometry and intracellular cytokine data are available through the FlowRepository website (ID FR-FCM-Z4KB). The images derived from the Allen Human Brain Atlas can be accessed at https://human.brain-map.org/. Specific URLs to recreate the following figures are provided: Fig. 2b (https://human.brain-map.org/static/brainexplorer), Extended Data Fig. 8a (https://human.brain-map.org/microarray/search/show?search_type=user_selections&user_selection_mode=1) and Extended Data Fig. 8b (https://human.brain-map.org/microarray/gene/show/605), and source data are available. For all clinical measurements and cytokine levels (Extended Data Figs. 1, 2, 6 and 9d–f), source data are available. Source data are provided with this paper.

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Acknowledgements

The authors would like to thank T. Dawson, H. Xie, M. Patel and the rest of the staff members at the Human Immune Monitoring Center at the Icahn School of Medicine for sample management and their help conducting omics assays. Furthermore, we would like to thank M. Garcia-Barros and R. Brody from the Biorepository and Pathology Core at the Icahn School of Medicine for immunohistochemistry staining. S.P. acknowledges support by the National Cancer Institute (NCI) (R01 CA244899 and R01 CA252222) and receives research funding from Amgen, Celgene/Bristol Myers Squibb and Karyopharm. M.M. acknowledges support from the National Institute of Allergy and Infectious Diseases (U24 AI118644-05S1, U19 AI128949 and U19 AI118610), from the NCI (R01 CA254104, R01 CA257195 and P30 CA196521-05S2), from a Fast Grant (George Mason University), from the Gates Foundation and from the Samuel Waxman Cancer Research Foundation. J.B. acknowledges support from the NCI (R01 CA246239-01).

Author information

Authors and Affiliations

Authors

Contributions

S.P. provided investigation, conceptualization, methodology, analysis, resources and supervision review as well as edits of the manuscript. D.M., S.G., C.B.S., S.J. and S.P. were involved in different aspects of clinical care for the patient, including interpretation of imaging. O.V.O., A.A., B.U., S.K.S., A.R., J.D.B., M.M. and S.P. were involved in design, execution, interpretation and analysis of immunological and genomics assays. S.S., J.F.C., J.T.F. and M.F. were involved in design, execution, interpretation and analysis of (neuro)pathological studies. O.V.O., A.A., A.L. and S.P. conducted data analysis, including creation of figures. O.V.O., A.A., J.D.B., M.M., S.J. and S.P. contributed to the writing of the first manuscript draft, which was approved and edited by all co-authors.

Corresponding author

Correspondence to Samir Parekh.

Ethics declarations

Competing interests

O.V.O. has no relevant conflicts to disclose. A.A. has no relevant conflicts to disclose. B.U. has no relevant conflicts to disclose. S.S. has no relevant conflicts to disclose. S.S. is currently employed by Sema4 but was not working for the company at the time of preparation of the manuscript. D.M. has worked as a consultant for Bristol Myers Squibb, Celgene, Foundation Medicine, GSK, Janssen, Kinevant and Sanofi and has received grant and research support from Allogene, Amgen, Bristol Myers Squibb, Celgene, Janssen and Regeneron. D.M. is currently employed by Johnson & Johnson but was not working for the company at the time of preparation of the manuscript. S.G. has no relevant conflicts to disclose. J.T.F. has no relevant conflicts to disclose. J.F.C. has no relevant conflicts to disclose. C.B.S. is a member of the ciltacabtagene autoleucel Risk Evaluation and Mitigation Strategy advisory board. S.K.S. has no relevant conflicts to disclose. A.R. is currently employed by Immunai but was not working for the company at the time of preparation of the manuscript. A.L. has no relevant conflicts to disclose. J.D.B. has received consulting fees from Celldex, Genentech, Gilead, Janssen, Kite and Merck and has received research funding or reagents provided by Celldex, Genentech, Janssen, Kite and Merck. M.M. has no relevant conflicts to disclose. S.J. has received consulting fees from Bristol Myers Squibb, Janssen, Karyopharm, Merck, Sanofi and Takeda. S.P. receives research funding from Amgen, Celgene/Bristol Myers Squibb and Karyopharm and consulting fees from Foundation Medicine. All other authors declare no competing interests.

Additional information

Peer review information Nature Medicine thanks Leo Rasche, Eric Smith, Daniel Rubin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Saheli Sadanand was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Clinical course and biochemical parameters after CAR-T cell treatment.

The time periods associated with cytokine release syndrome (CRS), neutropenic fever and neurotoxicity are annotated in the individual subplots. All cytokine levels were determined in the peripheral blood. (a) Temperature curve. (b) Administration of relevant pharmacologic treatments during the period after CAR-T treatment. (c) Total leukocyte, lymphocyte, and neutrophil counts. (d) Time course of CRP level (mg/L). (e) Time course of ferritin level (ng/mL). (f) Time course of IL-18 level (pg/mL). (g) Time course of IL-2Ra (CD25) level (pg/mL).

Source data

Extended Data Fig. 2 Cytokine levels and time course after CAR-T cell treatment.

The time periods associated with cytokine release syndrome (CRS), neutropenic fever and neurotoxicity are annotated in the individual subplots. (a) Time course of IFN-gamma level (pg/mL). (b) Time course of TNF-alpha level (pg/mL). (c) Time course of IL-6 level (pg/mL). (d) Time course of IL-10 level (pg/mL). All measurements are from peripheral blood plasma. (e) Olink cytokine profiling of peripheral blood plasma at different time points after chimeric antigen receptor (CAR) T cell therapy. Values shown are normalized protein expression (NPX) values according the Olink protocol in log2 scale (high protein levels in red, low protein levels in blue).

Source data

Extended Data Fig. 3 MRI and Ioflupane single photon emission computed tomography imaging after the onset of neurotoxicity.

(a) MRI axial FLAIR (left) and T2 (right) images at the level of the deep brain nuclei (top) and the cerebral cortex (top), conducted at day 101 after CAR-T infusion. Images demonstrate small punctuate hyperintensities present on imaging prior to CAR-T therapy and putatively due to pre-existing microvascular damage. (b) Ioflupane (123-I) scan images, conducted at day 155 after CAR-T infusion, show normal uptake at the level of the basal ganglia.

Extended Data Fig. 4 Quantitative analysis of FDG-PET/CT images confirms decreased metabolism in caudate nucleus after CAR-T cell therapy.

(a) FDG-PET axial splash images pre (top) and post (bottom) CAR-T infusion. Shown is a spectral scale with high metabolism/perfusion in red, to low metabolism/perfusion in dark blue. (b) Quantitative analysis showing normalized Z-score for all available regions of the brain before (blue) and after (red) CAR-T infusion. The caudate is highlighted. The normalized score was calculated using MIMneuro, comparing the image with a library of 43 FDG neurologic controls (41-80 years old).

Extended Data Fig. 5 Mass cytometry characterizes the effector-memory phenotype of CAR-T cells over time.

(a) Representative mass cytometry (CyTOF) plots illustrating the gating strategy for identifying CAR-T cells and T cell subsets as shown in Figs. 1a, 1d and Extended Data Figure 5e. (b) UMAP representation of peripheral blood mononuclear cells (PBMC) collected at time points shown in (a) shows the clustering of major immune cell types. (c) Relative contribution of major immune cell types in samples at different time points. (d) Expression of canonical markers, showing accurate classification of major immune celI types. (e) CAR-T cell phenotype, as determined by expression of CCR7 and CD45RA, illustrating a high fraction of effector-memory T cells at all time points. Each bar corresponds to N = 1 sample collected from the patient. The UMAP plots visually illustrate the clustering of T cells and confirm low CCR7 and CD45RA expression on CAR-T cells.

Source data

Extended Data Fig. 6 Cytokine expression of peripheral blood CAR-T cells isolated at day 128 after treatment vs. healthy donor T cells.

(a) CAR-T cells isolated at day 128 after CAR-T infusion were stimulated with PMA/ionomycin and cytokine production was assessed with mass cytometry. Shown here is high expression of TNF-alpha, interferon-gamma and GM-CSF and lack of expression of IL-17 in CD4 + (left) and CD8 + (right) CAR-T cells. (b) Percentage of CAR-T cells (orange) and healthy donor (HD) T cells (blue) expressing the full set of cytokines tested before (UNSTIM) or after (STIM) stimulation with PMA/ionomycin. Each bar represents N = 1 sample analyzed from the patient or healthy donor.

Source data

Extended Data Fig. 7 Expression of canonical markers on CITE-seq data identifies and clusters major immune cell types.

(a) t-SNE plot representation of CITE-seq analysis of peripheral blood mononuclear cells before and after PMA/ionomycin stimulation. Clustering was determined by similarity network fusion (SNF) and Louvain clustering algorithm. Individual cells are colored by subject (healthy donor (HD), neurotoxicity patient (NEUROTOX) and 3 other patients on the same clinical trial without neurotoxicity (MM1, MM2, MM3). Highlighted are the major immune cell types (B cells, NK cells, CD8 + T cells, CD4 + T cells, CAR-T cells and monocytes). There is a small cluster of events that corresponds to multiplets or debris (centrally, not highlighted). (b) Expression level of canonical genes: CD8A, CD4, CD14, FCGR3A (CD16), CD19 and NCAM1 (CD56). In each case showing both mRNA (top) and ADT (antibody-derived tag, representation of protein level) (high = red, low = blue). Expression levels are normalized as described in the Methods.

Extended Data Fig. 8 Expression of BCMA in healthy donors of the Allen Brain Atlas and presence of CAR-T cells in CSF of patient.

(a) Microarray data on top illustrates the expression of TNFRSF17 (BCMA) in the caudate nucleus of 5 healthy brain donors. The bottom shows that regions of TNFRSF17 (BCMA) expression coincides with DRD1 (dopamine receptor D1) expression, a protein know to be highly specific for the caudate nucleus. Image credit: Allen Institute: © 2010 Allen Institute for Brain Science. Allen Human Brain Atlas; available from: human.brain-map.org. (b) Schematic representation showing the log2 intensity of TNFRSF17 (BCMA) RNA expression in a single patient from the Allen Brain Atlas. Image credit: Allen Institute: © 2010 Allen Institute for Brain Science. Allen Human Brain Atlas; available from: human.brain-map.org. (c) Quantitative representation of the Allen Brain Atlas data with boxplots (median, Q1 and Q3 quartiles, whiskers up to 1.5 x IQR) showing normalized expression (z-score) across all six donors for different brain structures (N = 6, total of 3,702 probes across 27 brain regions). The p-values shown correspond to a two-sided Mann-Whitney U test of striatum versus any other region (**: p < 0.001, ***: p < 0.0001, n.s.: p ≥ 0.05).

Source data

Extended Data Fig. 9 Presence and persistence of CAR-T cells in CSF of patient and cytokine profiling in peripheral blood plasma versus CSF after development of neurotoxicity.

(a) Representative plots showing the gating strategy on CSF to get to the T cell gate. (b) Flow cytometric data of cerebrospinal fluid from day 148 after CAR-T cell infusion, showing presence of CD4 + and CD8 + CAR-T cells. (c) Flow cytometric data of cerebrospinal fluid from day 155 after CAR-T cell infusion (that is after administration of intravenous cyclophosphamide and intrathecal cytarabine), showing persistent presence of CD4 + and CD8 + CAR-T cells. (d) Normalized protein expression (NPX) log2 values of all cytokines in the Olink Immuno-Oncology panel, in serum (top) and CSF (bottom) (high protein levels in red, low protein levels in blue). (e) Scatter plot showing overall correlation of cytokine levels in plasma versus CSF (Pearson correlation coefficient r = 0.70, two-sided p < 0.001). (f) The log2 fold change (FC) of CSF versus blood plasma in a healthy control (along x-axis) and the patient who developed neurotoxicity (along y-axis). Highlighted are a selection of cytokines that are overrepresented in the patient’s CSF compared to the healthy control data. Among the cytokines that are overrepresented, we note a set of cytokines suggesting T cell activation (for example GZMB, GZMA, IFN-γ, CD40L, CD8A, CD27, FASLG), cytokines that are induced by IFN-γ (for example CXCL5, CXCL10, CXCL11) and that are known to act as chemo-attractants for T cells (among other immune cell types), and cytokines that point to possible involvement of cells in the blood-brain barrier (BBB) (for example PDGFB, EGF and ANGPT1).

Source data

Extended Data Fig. 10 Immunohistochemistry showing BCMA protein expression in brain tissue of the patient and in a control brain.

(a) BCMA immunohistochemistry of the caudate nucleus subependymal region (10x magnification, left, scale bar 200 µm). Inset (40x magnification, right, scale bar 50 µm) shows high magnification image of astrocytes (top) and a neuron (bottom) that stained positive for BCMA, whereas surrounding cells were negative. Images shown are representative slides from the caudate nucleus from the patient described in this case report (N = 1). For each region stained, at least 3 slides were available. (b) BCMA immunohistochemistry of selected brain regions as annotated in the patient of interest (left) versus a control brain (right) from a subject who died due to non-neurologic illness (10x magnification (top), scale bar 200 µm and 20x magnification (middle, bottom), scale bar 100 µm). Images shown are representative slides from the patient described in this case report (N = 1), as well as a single control brain (N = 1). For each region stained, at least 3 slides were available. The experiment was repeated in a second control brain with similar results.

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Van Oekelen, O., Aleman, A., Upadhyaya, B. et al. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nat Med 27, 2099–2103 (2021). https://doi.org/10.1038/s41591-021-01564-7

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