EBV-targeted T-cell Immunotherapy Associated With Improvements in Progressive Multiple Sclerosis

Article

MRI revealed that participants who achieved sustained or confirmed disability improvement showed significantly less ventricular enlargement at 12 months.

ATA188, an investigational Epstein–Barr virus (EBV)-targeted T-cell immunotherapy being evaluated in the EMBOLD clinical trial (NCT03283826) for the treatment of progressive multiple sclerosis, demonstrated an ability to effect confirmed disability improvement, which was associated with brain volume change and normalized magnetization transfer ratio on magnetic resonance imaging (MRI), according to results presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) taking place October 26-28, 2022, in Amsterdam, the Netherlands.1

Of the 24 patients who received ATA188, 9 achieved sustained disability improvement (SDI) either within a year of treatment or during the open-label extension (OLE), 7 participants achieved confirmed disability improvement (CDI), and 13 participants showed a stable Expanded Disability Status Scale (EDSS) score. All 5 participants continuing in OLE who have achieved CDI have maintained CDI for a range of 23.8 to 36.7 months (median, 27.5), having been followed for up to 46.5 months. It was noted that 4 of the 24 patients dosed showed confirmed disability progression. In terms of safety, there have been no adverse events greater than grade 3, dose-limiting toxicities, cytokine release syndrome, or graft versus host disease in the OLE, as of September 2022.

MRI revealed that participants who achieved SDI showed significantly less ventricular enlargement at 12 months (P = .019), with those who achieved CDI showing a similar trend (P = .108), compared to participants who did not. Percentage brain volume change (PBVC) measurements indicated that achieving CDI was associated with significantly less brain atrophy over time compared to those not achieving CDI in a longitudinal analysis through 42 months (95% CI, 0.02-0.66; P = .037). Ventricular enlargement measurements measured by percentage ventricular volume change (PVVC) showed a similar trend over time (95% CI, -0.6–0.03; P = .074). Measurements in unenhancing T2 lesions showed that achievement of CDI was associated with significantly increased myelin density on normalized magnetic transfer ratio (nMTR) over time in a longitudinal analysis through 42 months (95% CI, 0.05-0.24; P = .005). nMTR also revealed a similar trend for normal appearing brain tissue (95% CI, -0.04–0.35; P = .112).

“New biomarker imaging data presented at ECTRIMS suggest brain structural changes and potential remyelination may underlie clinical disability improvements observed with ATA188 treatment,” AJ Joshi, MD, chief medical officer, Atara, said in a statement regarding the data.2 “We are pleased to see a majority of patients experiencing either long term durability of CDI based on EDSS improvement or long-term stability in EDSS, which would also represent a transformational profile relative to the expected natural course of the disease.”

In terms of MRI measurements, no significant differences were observed in PBVC (P = .538) and thalamus volume change (P = .529) between patients who achieved SDI during the first 12 months post-treatment and those who did not. Furthermore, the change in PBVC for participants who achieved CDI at any point was not significantly different at the 12-month mark compared with those who did not (P = .437).

The randomized, placebo-controlled phase 2 portion of the EMBOLD trial is ongoing. The investigators concluded that while the results reported from the phase 1 portion above are promising, the phase 2 data will be needed for additional confirmation. The trial is estimated to reach primary completion in July 2023.

REFERENCES
1. Noteboom S. Long-term disability improvement during EBV-targeted T-cell immunotherapy ATA188 is related to brain volume change and normalisedmagnetisation transfer ratio in T2 lesions. Presented at: 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). October 26-28, 2022; Amsterdam, the Netherlands. Abstract EP1242
2. Atara Biotherapeutics presents new MRI and updated open-label extension data from phase 1 study of ATA188 in progressive multiple sclerosis at ECTRIMS 2022. News release. Atara Biotherapeutics, Inc. October 26, 2022. https://investors.atarabio.com/news-events/press-releases/detail/292/atara-biotherapeutics-presents-new-mri-and-updated 

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