Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis
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
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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Clinical Research and Public Health 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 5

Relationship between EBV-specific CD8+ T cell reactivity of T cell product and clinical response to T cell therapy.

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Relationship between EBV-specific CD8+ T cell reactivity of T cell produ...
(A) Relationship between clinical response and the frequency of LMP/EBNA1-specific CD8+ T cells in the T cell product. Participants were grouped into those receiving T cell therapy with >5% of CD8+ T cells expressing a given individual cytokine (CD107a, IFN-γ, TNF-α, or IL-2) after recall with a peptide pool of CD8+ T cell epitopes encoded by EBNA1, LMP1, and LMP2A (strong reactivity) and those receiving T cell therapy with <5% reactivity (weak reactivity). A clinical response to T cell therapy was defined as clinical improvement at week 27 (the last clinical assessment in the study) compared with week 1 (immediately prior to the first T cell infusion). IL-2 expression was not assessed in the cells for participant 12. P values were calculated with Fisher’s exact test; n = 10 for CD107a, IFN-γ, and TNF-α; n = 9 for IL-2. (B) Proportion of LMP/EBNA1-specific CD8+ T cells expressing all the different combinations of the 4 cytokines (CD107a, IFN-γ, TNF-α, and IL-2) in the participants showing clinical improvement (Responder) compared with the participants not showing clinical improvement (Non-responder). This analysis was not able to be performed on the cells for participant 1 (n = 9). There was a higher proportion of EBV-specific polyfunctional T cells (expressing CD107a, IFN-γ, TNF-α, and IL-2) in the CD8+ T cells within the therapy administered to participants showing clinical improvement than in the therapy administered to participants not showing clinical improvement (P < 0.0001, multiple 2-tailed t test with the Holm-Sidak correction for multiple comparisons). Horizontal bars represent the mean and standard error of the mean.