MedicalResearch.com Interview with:
Dietmar P. Berger, MD, PhD
Head of Global R&D
MedicalResearch.com: What is the background for this study?
Response: Epstein-Barr virus (EBV) is present in B lymphocytes, plasma cells and epithelial cells of over 95% of individuals over the age of 40. Multiple studies have shown that nearly all patients with Multiple Sclerosis (MS) are EBV positive, including a recent presentation at the 2018 ECTRIMS Congress in Berlin that showed 100% of MS patients are positive for EBV (Ruprecht et. al). Current B cell directed therapies such as anti-CD20 therapies have demonstrated an effect on Multiple Sclerosis activity. These therapies work by depleting B cells including those infected by EBV.
Our belief is that loss of EBV-specific T cell function (e.g., T cell exhaustion) occurs in patients who develop Multiple Sclerosis, which results in the accumulation of EBV infected B and plasma cells in the CNS leading to the autoreactive immune cycle seen in MS patients. The increasing evidence of a link between EBV infection and the development of MS led to the initiation of a Phase 1 study to investigate the use of an autologous T-cell immunotherapy (ATA190) to selectively target and deplete EBV infected cells in patients with progressive MS.
As T cell immunotherapies (like ATA190) are designed to penetrate the central nervous system, this approach was felt to be particularly useful in Multiple Sclerosis where the inflammatory response and infected B lymphocytes and plasma cells are inaccessible inside the CNS to the vast majority of classic targeted agents.
MedicalResearch.com: What are the main findings?
Response: This Phase 1 open-label, uncontrolled study evaluated escalating doses of ATA190 in ten patients, five with primary and five with secondary progressive Multiple Sclerosis. Safety and efficacy were monitored for up to 27 weeks and included Expanded Disability Status Scale (EDSS) score, fatigue, cognitive and other neurological assessments as well as analysis of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) immunoglobulin G (IgG) production. Prior to ATA190 T-cell immunotherapy, patients had experienced progressive neurological deterioration for a mean of 10.1 years.
ATA190 was well-tolerated and no severe adverse events were observed in the study. Adverse events of grade 1 or 2 severity occurred in 2 participants, with one grade 1 dysgeusia definitely related to treatment. Seven patients in the study showed symptomatic and objective neurological improvement, which commenced two to 14 weeks after the first infusion. Reduction in fatigue, one of the most frequent and disabling symptoms of Multiple Sclerosis, was a consistent and prominent feature in patients showing neurological improvement.
Reactivity of ATA190 against target EBV antigens (EBV reactivity) as well as other mechanistic markers of T cell function were assessed. Six participants in the study who received ATA190 with strong EBV reactivity experienced clinical improvement, including three with decreased EDSS scores. One of four participants who received ATA190 with weak EBV reactivity showed improvement and no change in EDSS score was observed. One of ten patients had neurological deterioration during the study.
MedicalResearch.com: What should readers take away from your report?
Response: Although this was a small, open-label study, it lends support to the EBV hypothesis in Multiple Sclerosis and suggests that a T cell immunotherapy targeting EBV infected B lymphocytes and plasma cells may be safe and have a positive effect on disease activity in patients with progressive Multiple Sclerosis where there is a high unmet need.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We are investigating randomized, controlled studies in progressive MS with T cell immunotherapy-based approaches, continuing to address questions including safety, demonstration of a biological effect, penetration into the CNS and effect on clinical measures including disability.
It will be useful to compare the effect of ATA190, an autologous T-cell immunotherapy, with that of an allogeneic, donor derived T-cell immunotherapy (ATA188) targeting EBV.
MedicalResearch.com: Is there anything else you would like to add?
Response: The Phase 1 clinical study was conducted by Atara’s collaborating investigators at QIMR Berghofer Medical Research Institute and The University of Queensland with funding from MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd and donations from private individuals. Findings were recently reported in an article online and to be published in the December 2018 issue of JCI Insight. Atara Biotherapeutics is advancing an ongoing Phase 1 off-the-shelf, allogeneic ATA188 study in patients with progressive MS across clinical sites in the U.S. and Australia and plans to initiate a randomized autologous ATA190 study in progressive MS patients.
Pender MP1,2,3, Csurhes PA1,4, Smith C3, Douglas NL1,2, Neller MA3, Matthews KK3, Beagley L3, Rehan S3, Crooks P3, Hopkins TJ5, Blum S1,2, Green KA1,2, Ioannides ZA1,2, Swayne A1,2, Aftab BT6, Hooper KD1,2, Burrows SR1,3, Thompson KM7,8, Coulthard A1,9, Khanna R1,3.
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