Sustained Clinical Improvement in a Subset of Patients With Progressive Multiple Sclerosis Treated With Epstein-Barr Virus-Specific T Cell Therapy.

Background: Increasing evidence indicates a role for Epstein-Barr virus (EBV) in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the central nervous system because of defective cytotoxic CD8+ T cell immunity. We have previously reported results of a phase I clinical trial of autologous EBV-specific T cell therapy in MS 6 months after treatment. Objective: To investigate longer-term outcomes in MS patients who received autologous EBV-specific T cell therapy. Methods: We assessed participants 2 and 3 years after completion of T cell therapy. Results: We collected data from all 10 treated participants at year 2 and from 9 participants at year 3. No serious treatment-related adverse events were observed. Four participants had at least some sustained clinical improvement at year 2, including reduced fatigue in three participants, and reduced Expanded Disability Status Scale score in two participants. Three participants experienced a sustained improvement in at least some symptoms at year 3. More sustained improvement was associated with higher EBV-specific CD8+ T cell reactivity in the administered T cell product. Conclusion: Autologous EBV-specific T cell therapy is well-tolerated, and some degree of clinical improvement can be sustained for up to 3 years after treatment.

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

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.

Memory instruction interacts with both visual and motoric inhibition of return.

In the item-method directed forgetting paradigm, the magnitude of inhibition of return (IOR) is larger after an instruction to forget (F) than after an instruction to remember (R). In the present experiments, we further investigated this increased magnitude of IOR after F than after R memory instructions, to determine whether this F > R IOR pattern occurs only for the motoric form of IOR, as predicted, or also for the visual form. In three experiments, words were presented in one of two peripheral locations, followed by either an F or an R memory instruction. Then, a target appeared either at the same location as the previous word or at the other location. In Experiment 1, participants maintained fixation throughout the trial until the target appeared, at which point they made a saccade to the target. In Experiment 2, they maintained fixation throughout the entire trial and made a manual localization response to the target. The F > R IOR difference in reaction times occurred for both the saccadic and manual responses, suggesting that memory instructions modify both motoric and visual forms of IOR. In Experiment 3, participants made a perceptual discrimination response to report the identity of a target while the eyes remained fixed. The F > R IOR difference also occurred for these manual discrimination responses, increasing our confidence that memory instructions modify the visual form of IOR. We relate our findings to postulated differences in attentional withdrawal following F and R instructions and consider the implications of the findings for successful forgetting.

Effects of memory instruction on attention and information processing: Further investigation of inhibition of return in item-method directed forgetting.

In the item-method directed-forgetting paradigm, the magnitude of inhibition of return (IOR) is larger after an instruction to forget (F) than after an instruction to remember (R). In the present experiments, we further investigated this increased magnitude of IOR after F as compared to R memory instructions (dubbed the F > R IOR difference), in order to understand both the consequences for information processing and the purpose of the differential withdrawal of attention that results in this difference. Words were presented in one of four peripheral locations, followed by either an F or an R memory instruction. Then, a target appeared in either the same location as the previous word or one of the other locations. The results showed that the F > R IOR difference cannot be explained by attentional momentum (Exp. 1), that the spatial compatibility of the response options with target locations is not necessary for the F > R IOR difference to emerge (Exp. 2), and that the F > R IOR difference is location-specific rather than response-specific (Exp. 3). These results are consistent with the view that F > R IOR represents a bias against responding to information emanating from an unreliable source (Taylor & Fawcett, 2011).

Tag, you're it: tagging as an alternative to yes/no recognition in item method directed forgetting.

The current study contrasted a standard yes/no recognition task with a tagging recognition task in the context of an item-method directed forgetting paradigm. During the study phase, a series of words was presented one at a time, each followed by an instruction to remember (R) or forget (F). The retention of R and F study words was tested using either a typical yes/no recognition task or a tagging recognition task in which participants labeled each word as "R", "F" or "New". The directed forgetting effect observed in each task was equivalent in magnitude. However, the tagging recognition task afforded an additional analysis of the errors of misattribution that was not possible with the more typical yes/no recognition task. Interestingly, when falsely recognizing a Foil word, participants were more likely to assign an "F" tag than an "R" tag. These errors of misattribution are consistent with existing accounts of directed forgetting that suggest R words are better encoded than F words. We argue for the utility of the tagging procedure, given it does not alter the directed forgetting effect normally seen with yes/no recognition but provides additional information about errors of misattribution.