Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis
Michael P. Pender, … , Alan Coulthard, Rajiv Khanna
Michael P. Pender, … , Alan Coulthard, Rajiv Khanna
Published November 15, 2018
Citation Information: JCI Insight. 2018;3(22):e124714. https://doi.org/10.1172/jci.insight.124714.
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Clinical Medicine Clinical trials Neuroscience

Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis

Abstract

BACKGROUND. Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy. METHODS. An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro–expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses. RESULTS. Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test). CONCLUSION. EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS. TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry, ACTRN12615000422527. FUNDING. MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.

Authors

Michael P. Pender, Peter A. Csurhes, Corey Smith, Nanette L. Douglas, Michelle A. Neller, Katherine K. Matthews, Leone Beagley, Sweera Rehan, Pauline Crooks, Tracey J. Hopkins, Stefan Blum, Kerryn A. Green, Zara A. Ioannides, Andrew Swayne, Blake T. Aftab, Kaye D. Hooper, Scott R. Burrows, Kate M. Thompson, Alan Coulthard, Rajiv Khanna

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Figure 3

Fatigue score and cognitive function after T cell therapy.

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Fatigue score and cognitive function after T cell therapy. (A) Fatigue S...
(A) Fatigue Severity Scale (FSS) (ref. 22) score at week 1, immediately before the first T cell infusion, and at week 27 (n = 10). A total score of 36 (indicated by dotted horizontal line in B) or more suggests that a person is suffering from fatigue. The maximum score is 63 and the minimum score is 9. Horizontal bars indicate the medians and interquartile range. P = 0.0547, Wilcoxon matched-pairs signed-rank test. (B) FSS score over time in each of the treated patients. Vertical arrows indicate successive T cell infusions of 5 × 106, 1 × 107, 1.5 × 107, and 2 × 107 cells. Red lines indicate patients showing no symptomatic improvement (participants 2, 6, and 8) and green lines indicate patients showing symptomatic improvement (participants 1, 3, 4, 5, 9, 12, and 13). The participant showing the greatest reduction in fatigue (participant 5) received T cells with the highest degree of EBV reactivity (45.45% of CD8+ T cells). (C) Standardized change in scores (means with standard deviations indicated by horizontal bars) (n = 10) for the individual components of the comprehensive neuropsychological test battery (week 27 minus venesection visit) after T cell therapy. For each component, standardization was performed by dividing the change in test score from week 1 to week 27 by the standard deviation of the week 1 group mean. For example, a score of 1 indicates that the week 27 score is 1 standard deviation higher than the week 1 score. The obtained Z-scores for 4 variables were inverted (CTIP Reaction Time variables and BDI) to ensure consistency in the direction of change across all plots so that positive Z-scores indicate improved performance and negative Z-scores indicate decreased performance. COWAT, Controlled Oral Word Association Test; JOLO, Judgement of Line Orientation; CVLT-TL, California Verbal Learning Test – Total Learning; CVLT-DR, California Verbal Learning Test – Delayed Recall; BVMT-TL, Brief Visual Memory Test – Total Learning; BVMT-DR, Brief Visual Memory Test – Delayed Recall; SDMT, Symbol Digit Modalities Test; PASAT, Paced Auditory Serial Addition Test; DKEFS-CS, Delis–Kaplan Executive Function System – Correct Sorts; DKEFS-DS, Delis–Kaplan Executive Function System – Description Score; RT, Reaction Time; BDI, Beck Depression Inventory – Fast Screen.