For many years, medical researchers have known that Epstein-Barr virus (EBV), a common infection that can cause mononucleosis as well as certain rare cancers, is a risk factor for the development of multiple sclerosis (MS).i With new research suggesting that EBV may, in fact, be a necessary precursor to MS, it is time to consider the therapeutic implications of targeting EBV.ii,iii
Understanding EBV and its role in MS
MS is a serious autoimmune disease which causes damage to the central nervous system (CNS).iv Current treatments aim to modulate a dysregulated immune system with many having significant impacts on relapse rate but very few, if any, are able to fundamentally alter disease progression. Identifying the underlying cause of MS may be the key to changing this. Although several genetic and environmental risk factors have been found, identifying a common underlying driver of MS has been elusive.v However, recent evidence suggests this may no longer be the case.
EBV infects over 95% of people by the age of 40, and while it can remain dormant in the body throughout life, most infections are inactive and never detected because healthy immune systems can keep EBV at bay. When the immune system isn’t functioning normally, uncontrolled EBV may drive an autoimmune reaction that causes the body to attack itself, as it does in MS.vi,vii
Earlier this year, two landmark, peer-reviewed studies published in Science and Nature provided strong evidence confirming the role of EBV in driving the pathophysiology of MS. Bjornevik et al. showed that EBV is what initiates the disease in susceptible individuals with a 32-fold increased risk after infection and Lanz et al. described a direct molecular, or mechanistic, basis for how EBV infection may cause the development of MS. These groundbreaking publications provide strong support for a critical link between EBV and MS and also provide strong rationale for selectively targeting EBV-infected B cells and plasma cells as a therapeutic target.ii,iii
Targeting EBV infection to treat progressive forms of MS
An estimated 2.8 million people worldwide are living with MS, including roughly 900,000 people in the U.S. alone.viii,ix Current treatments predominately aim to reduce relapse rate but very few, if any, are able to fundamentally alter disease progression. There are 1.2 million people around the world living with progressive MS whose needs remain unmet.viii,x,xi
This unmet need, coupled with the recent landmark research, continues to drive Atara Biotherapeutics’ investigational approach. By specifically targeting what evidence suggests may be the underlying driver of MS, EBV-infected cells, our goal is to fundamentally alter MS disease progression.
Developing allogeneic off-the-shelf cell therapies for progressive forms of MS
Using cell-based immunotherapies to harness the power of the immune system to target EBV-diseased cells has been described as the next potential evolution currently under investigation for severe diseases such as autoimmune conditions and certain cancers.xii,xiii
But the frontiers of medicine continue to be pushed further as the field evaluates off-the-shelf cell-based therapies that use T cells from unrelated (or allogeneic) healthy donors to directly target virally infected cells in a patient.
Building on the growing body of evidence linking EBV to MS, Atara’s EBV T-cell immunotherapy platform aims to leverage the natural attributes of EBV T cells — including trafficking to the site of disease, specificity for disease targets with a low likelihood to harm normal cells, and the ability to persist in the body long enough to fight the disease — without genetic modification of the T-cell receptor.xiv ATA188, Atara’s investigational off-the-shelf, allogeneic T-cell immunotherapy aims to specifically target EBV-infected B cells and plasma cells in people with progressive forms of MS and is currently in a Phase 2 study.
Additionally, Atara’s manufacturing technology using stirred-tank bioreactors has the potential to produce up to ~20,000 doses from a single donor, ready in advance of patient need. Together, these elements represent a unique investigative approach with the potential to address the unmet needs for patients with progressive forms of MS.
Investigating the potential of EBV T cells
Looking at the overall landscape for MS therapeutics, we learned over time about the important role of T and B cells in this disease. A range of therapies have been developed to sequester, inhibit, or deplete these immune cells. However, recent evidence suggests that EBV is the leading cause of MS from onset to progression of the disease. Specifically targeting EBV infected B cells represents a new targeted investigational therapeutic approach.
To learn more about Atara’s EBV T-cell platform technology, visit: https://www.atarabio.com/science-and-technology/
i Epstein-Barr and infectious mononucleosis (mono). (n.d.). Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/epstein-barr/index.html
ii Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J. S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G. S., Bartley, C. M., Schubert, R. D., Hawes, I. A., Vazquez, S. E., Iyer, M., Zuchero, J. B., Teegen, B., Dunn, J. E., Lock, C. B., Kipp, L. B., . . . Robinson, W. H. (2022). Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature, 603(7900), 321–327. https://doi.org/10.1038/s41586-022-04432-7
iii Bjornevik, K., Cortese, M., Healy, B. C., Kuhle, J., Mina, M. J., Leng, Y., Elledge, S. J., Niebuhr, D. W., Scher, A. I., Munger, K. L., & Ascherio, A. (2022). Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 375(6578), 296–301. https://doi.org/10.1126/science.abj8222
iv National Multiple Sclerosis Society. (n.d.). National Multiple Sclerosis Society. Retrieved July 15, 2022, from https://www.nationalmssociety.org
v Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav. 2015;5(9):e00362. doi:10.1002/brb3.362
vi Auwaerter, P. (2021). Epstein-Barr virus. Johns Hopkins ABX Guide. https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540208/all/Epstein_Barr_Virus
vii Long, H. M., Meckiff, B. J., & Taylor, G. S. (2019). The T-cell Response to Epstein-Barr Virus–New Tricks From an Old Dog. Frontiers in Immunology, 10. https://doi.org/10.3389/fimmu.2019.02193
viii MS International Federation. (2020, September). Atlas of MS (3rd edition). https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf
ix McGinley, M. P., Goldschmidt, C. H., & Rae-Grant, A. D. (2021). Diagnosis and Treatment of Multiple Sclerosis. JAMA, 325(8), 765. https://doi.org/10.1001/jama.2020.26858
x Salter A, Thomas NP, Tyry T, Cutter GR, Marri RA. A contemporary profile of primary progressive multiple sclerosis participants from the NARCOMS Registry. Mult Scler. 2018;24(7):951-962. doi:10.1177/1352458517711274
xi Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006 Mar;129(Pt 3):606-16
xii Taefehshokr N, Baradaran B, Baghbanzadeh, et al. Promising approaches in cancer immunotherapy. Immunobiology. 2020;225(2):151875. doi:10.1016/j.imbio.2019.11.010.
xiii Weber EW, Maus MV, Mackall CL. The emerging landscape of immune cell therapies. Cell. 2020 Apr 2;181(1):46-62. doi: 10.1016/j.cell.2020.03.001.
xiv Rosato, P. C., Wijeyesinghe, S., Stolley, J. M., Nelson, C. E., Davis, R. L., Manlove, L. S., Pennell, C. A., Blazar, B. R., Chen, C. C., Geller, M. A., Vezys, V., & Masopust, D. (2019). Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nature communications, 10(1), 567. https://doi.org/10.1038/s41467-019-08534-1