ATA188 shows promise against MS in early phase trial
Click Here to Manage Email Alerts
A novel allogeneic Epstein-Barr virus-targeted T-cell immunotherapy in early development was well-tolerated and led to sustained disability improvements in patients with progressive forms of MS, researchers reported at MSVirtual2020.
“There is a growing body of evidence linking EBV infection of memory B cells and the pathogenesis of MS,” Jakob Dupont, MD, global head of research and development at Atara Biotherapeutics, told Healio Neurology. “EBV infection has been reported in up to 100% of MS patients and is the only risk factor identified to date that appears to be necessary for MS.”
Dupont explained that EBV-infected cells — particularly B memory cells — play an important role in the “immune cascade” responsible for both relapsing and progressive forms of MS.
“The success of interventions that deplete all peripheral B cells underscores the importance of these cells in MS pathophysiology,” he said. “ATA188 offers a unique approach with the advantage of selectively targeting EBV-infected B cells and plasma cells in the circulation and in the central nervous system.”
In a phase 1a, multicenter, open-label study, researchers tested ATA188 in patients with progressive forms of MS to assess its safety and early signs of efficacy, and to narrow down the right dosage in an ongoing randomized clinical trial. ATA188 is sourced from healthy EBV-seropositive donors to generate EBV-targeting T-cells, and the therapy is administered after patients with MS are matched through human leukocyte antigen (HLA) typing.
“The T-cells are sensitized against specific EBV antigens so they can precisely target EBV-infected cells implicated in MS,” Dupont explained. “ATA188 is available as a pre-manufactured inventory that can be readily selected for each patient based on an appropriate HLA restriction and allele profile and then delivered for administration in about 3 days. It’s is also easy to administer in a 5- to 10-minute IV infusion in the outpatient setting with brief observation periods.”
ATA188 proved to be safe enough to continue testing in the randomized clinical trial, researchers said. Patients taking higher doses were more likely to achieve sustained disability improvements (SDI), defined as clinically significant improvement on the Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk scale (T25FW), confirmed at two consecutive timepoints. The improvements were primarily driven by EDSS scores rather than those from the T25FW. Those with SDI at 12 months tended to show improvements in fatigue and physical function and better scores on the MS Walking Scale than those who did not show SDI.
The researchers also found that patients who achieved SDI at any timepoint maintained it at all future timepoints — with one patient achieving SDI at up to 24 months in an open-label extension phase.
“We are very encouraged to see that patients receiving ATA188 who achieved sustained disability improvement maintained it at all future time points measured in this study,” Dupont said. “To observe such consistent sustained disability improvement over time in an early stage study is promising, and we look forward to confirming these findings in the larger randomized controlled trial, which is currently enrolling.”
Perspective
Back to Top
Several lines of evidence support a role for EBV in the etiology and/or pathogenesis of MS. The intervention used in this study was innovative — administration of allogeneic T-cells targeting EBV. The main goal of this open-label, dose-escalation, dose-finding, phase 1a trial was to assess safety and tolerability, both of which appeared good. There was an encouraging suggestion of benefit on disability and patient-reported outcomes, but those results must be interpreted with caution. These results support proceeding with a randomized, controlled, blinded trial to more definitively examine efficacy — which is ongoing.
Collapse
Bar-Or A, et al. Abstract P0226. Presented at: MSVirtual2020; Sept. 11-13, 2020 (virtual meeting).
Read more about
Click Here to Manage Email Alerts