AJ Joshi, MD

"There’s nothing new about the concept. It’s the evidence now that this is causative. I would expect a lot of additional research to start to come up. What are the mechanisms of disability progression? We see it happening—why don’t other therapies work to prevent progression? Why can we only slow it down, as opposed to reversing it?"

identified Epstein-Barr virus (EBV) as the leading cause of 

, a new landmark study extended these findings by providing insight on the mechanistic link between the two.

 While genetic and environmental factors play a role, it has been postulated that EBV triggers a patient’s immune cells to erroneously attack myelin. Industry leaders, such as Atara Biotherapeutics, have already turned their attention to targeting EBV antigens. Its investigational agent, ATA188, has shown promising early results as a potential treatment for progressive MS, a form that has been challenging to treat, with few options available.

Atara lauded the second high impact study, claiming that these findings validate molecular mimicry as one of the leading mechanisms of EBV-mediated MS, which occurs when fragments of the virus share sequence of structural similarities with certain brain proteins. 

, chief medical officer, Atara, believes there are other potential outlets for ATA188, mainly in other relapsing forms of the disease.

 sat down with Joshi to discuss the future of EBV and MS-related research, including the role of ATA188, going forward. He provided insight on how the community can build upon what’s been recently documented and the questions that still need to be answered.

REFERENCE
1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. 

Published online January 13, 2022. doi:10.1126/science.abj8222
2. Lanz TV, Brewer RC, Robinson WH, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM
3. New landmark study provides long-sought mechanistic link between EBV and multiple sclerosis, extending findings from recent paper in 

that identified EBV as the leading cause of multiple sclerosis. News release. January 24, 2022. Accessed February 15, 2022. https://www.businesswire.com/news/home/20220122005025/en/New-Landmark-Nature-Study-Provides-Long-Sought-Mechanistic-Link-Between-EBV-and-Multiple-Sclerosis-Extending-Findings-from-Recent-Paper-in-Science-That-Identified-EBV-as-the-Leading-Cause-of-Multiple-Sclerosis

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The chief medical officer at Atara Biotherapeutics provided insight on the future direction of its investigational agent ATA188 following new data that suggested a link between Epstein-Barr virus and multiple sclerosis. [WATCH TIME: 4 minutes]

Next Steps for ATA188, Research Related to EBV and Multiple Sclerosis: AJ Joshi, MD

"This is not pan B-cell depletion or pan past plasma cell depletion. It’s only attacking the bad players, essentially. It’s these EBV-infected B-cells and plasma cells that are felt to be the causes of the autoimmune cascade and the pathology we’re seeing."

Despite the ever-expanding toolbox of treatment options for patients with relapsing forms of multiple sclerosis (MS), there has been little traction in terms of therapeutics for those with progressive forms of the disease. ATA188, an investigational agent developed by Atara Biotherapeutics, has been among the promising agents in the pipeline for progressive MS, after phase 1 open-label results suggested the therapy has a 

Atara’s therapeutic is unique in that it targets Epstein-Barr virus (EBV)-infected B-cells and plasma cells in the central nervous system that may catalyze autoimmune responses and MS pathophysiology. It has gained even more attention because of 2 recent publications, one in 

that have bolstered further solidified the idea that EBV is the leading cause of MS. The first analysis by Albert Ascherio, MD, DrPH, et al included data from more than 10 million individuals and found 32-fold increase in MS incidence in patients who’ve contracted EBV.

The company plans to release new data from its ongoing phase 2 EMBOLD study (NCT03283826) sometime in 2022. Ahead of its highly anticipated readout, 

, chief medical officer, Atara. Joshi provided insight on the mechanistic action of ATA188, how it specifically tackles MS, and the specific takeaways clinicians should be looking for in the upcoming data readout.

REFERENCES
1. Bar-Or A, Pender MP, Hodgkinson SJ, et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis. Presented at ECTRIMS Congress; October 13-15, 2021; Poster P638.

2. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. 

Published online January 13, 2022. doi:10.1126/science.abj8222

The chief medical officer at Atara Biotherapeutics discussed the investigational agent ATA188, its mechanism to treat multiple sclerosis, and what to look for in its upcoming EMBOLD trial data readout. [WATCH TIME: 4 minutes]

ATA188, Targeting EBV Antigens to Treat Progressive MS: AJ Joshi, MD

"The Nature publication is focusing in on the how. EBV is the leading cause, how is it happening? What it ends up focusing on in that dataset is the molecular mimicry."

Less than a month ago, excitement was generated in the 

which suggested that Epstein-Barr virus (EBV), also known as human herpesvirus 4, may be the leading cause for MS, lending credence to a long-held theory in the field.

 Shortly after, a second paper extended these findings, by providing a mechanistic basis for how EBV infection can trigger a patient’s immune cells to attack self-tissue in the central nervous system.

In that study, researchers identified a type of antibody isolated from the cerebrospinal fluid (CSF) of patients with MS, which strongly binds to an EBV protein, EBNA1, and cross-reacts with the central nervous system protein GlialCAM. In a mouse model, the group also demonstrated that immunization with EBNA1 of MS exacerbated the disease and generated a strong antibody response against GlialCAM and EBNA1, enhancing immune cell infiltration and demyelination.

Atara Biotherapeutics has utilized its novel EBV T-cell platform to develop transformative therapies, namely ATA188, to tackle MS at its source. ATA188 targets key epitopes of these antigens, including EBNA1, and has produced positive phase 2 results in patients with progressive MS, a patient population that desperately lacks treatment options. AJ Joshi, MD, chief medical officer, Atara, sat down with 

® to discuss the importance of the recently published paper in 

and how it builds on what clinicians have previously observed.

REFERENCES
1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. 

2. New landmark study provides long-sought mechanistic link between EBV and multiple sclerosis, extending findings from recent paper in 

that identified EBV as the leading cause of multiple sclerosis. News release. January 24, 2022. Accessed February 9, 2022. 

https://www.businesswire.com/news/home/20220122005025/en/New-Landmark-Nature-Study-Provides-Long-Sought-Mechanistic-Link-Between-EBV-and-Multiple-Sclerosis-Extending-Findings-from-Recent-Paper-in-Science-That-Identified-EBV-as-the-Leading-Cause-of-Multiple-Sclerosis

The chief medical officer at Atara Biotherapeutics detailed the clinical significance of a recently published paper in Nature that adds to the evidence that Epstein-Barr virus is the leading cause of multiple sclerosis. [WATCH TIME: 3 minutes]


AJ Joshi, MD

Articles

Next Steps for ATA188, Research Related to EBV and Multiple Sclerosis: AJ Joshi, MD

ATA188, Targeting EBV Antigens to Treat Progressive MS: AJ Joshi, MD

Understanding the Epidemiological Connection Between MS and Epstein-Barr Virus: AJ Joshi, MD

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