By the time the pharmaceutical industry began exploring B cell depletion as a treatment for relapsing-remitting multiple sclerosis (MS), Amit Bar-Or, MD, FRCPC, was already well on the way with his own B cell research.
"Our lab and a few others had been interested in B cells’ role in MS for some time, so we were very happy to get involved in these studies,” explains Dr. Bar-Or, Chief of the MS Division at the University of Pennsylvania’s Department of Neurology and Director of Penn’s Center for Neuroinflammation and Experimental Therapeutics (CNET).
The ensuing work led researchers to a crucial revelation that has propelled both MS research and treatment. “Contrary to what many believed, we discovered that the B cells themselves, and not the antibodies they produced, were responsible for triggering relapses in these patients,” Dr. Bar-Or shares.
Limiting Multiple Sclerosis Relapses and Progression
A little over 10 years later, Ocrevus, an anti-CD20 therapy and the first FDA-approved treatment for both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS), came to market. And while Ocrevus isn’t the only drug available for people with RRMS, Dr. Bar-Or shares that it is one of the best to match the profile of a desirable MS treatment: easy to take, generally safe, well-tolerated and highly effective. The fact that it has some capacity to also limit the progression of PPMS is an important added benefit, though he cautions that it can’t fix what’s already broken.
“While we used to think that T cells of the immune system were the main triggers of MS relapses, we now understand that relapses involve important interactions between B cells and T cells that take place outside the central nervous system (CNS),” Dr. Bar-Or explains. “These interactions result in waves of activated immune cells tracking into the CNS and causing inflammation and damage. Remissions between these attacks can be partial or complete and the inflammation may leave residual damage, even after symptoms disappear.
“Ocrevus targets and eliminates many B cells that have the CD20 molecule on their surface,” he continues. “By eliminating them, the B cells are less likely to overly activate the T cells thereby limiting new relapses and CNS damage in individuals with MS.” To date, 700 people have been treated with this therapy at Penn Medicine. Two-thirds of these are individuals with RRMS and the balance have PPMS.
With RRMS now targeted quite effectively, Dr. Bar-Or and his colleagues at Penn’s CNET have turned much of their attention to gaining a better understanding for primary and secondary progressive MS.
Some people historically considered RRMS to be driven by the immune system in contrast to progressive MS being driven by degeneration,” says Dr. Bar-Or. “We’ve learned that progressive MS also most certainly involves important components of inflammation, but in these patients, we think the inflammation becomes compartmentalized within the CNS, ‘setting up shop’ there and contributing to progressive injury even when immune cell attacks from the periphery are no longer taking place.”
Transforming Care Through Precision Medicine
Dr. Bar-Or shares that there are currently 12 MS clinical trials taking place at the center, most of which are cutting-edge, early phase, higher-impact clinical trials. Through these, exciting new insights continue to be gained into how cells of the immune system interact with CNS cells to contribute to ongoing injury. These insights are starting to translate into new treatment approaches that will hopefully limit or stop these cellular interactions contributing to progressive injury. It’s an area where Penn is emerging as a global leader.
“Neuroinflammation is an area that is really transforming, and our center’s translational approach to understanding neuroinflammation across the age-span—as it relates to MS as well as a range of other conditions—is positioning us as one of the top programs,” says Dr. Bar-Or. “By developing and incorporating novel immune assays into well-designed clinical trials for MS, we’ve been able to gain at times surprising insights into disease mechanisms and develop biomarkers of response to therapy, while also evaluating the safety and efficacy of novel MS therapies.”
Recently, the center’s focus has shifted to the variances of MS at the biological level. “Subsequent studies have shown that people with MS are biologically different, in that the relative contribution of the immune cells (B and T) varies from patient to patient,” explains Dr. Bar-Or. “So, while many people are diagnosed with the same condition, important biological differences call for a more tailored treatment approach. What we are doing now is following people over time, collecting samples and measuring the state of their immune systems as part of a comprehensive biological approach to define what cellular combinations lead to each person’s MS activity and how to more precisely recommend the most appropriate immune therapy.
“Essentially, we’re unlocking the black box of MS…and that’s precision medicine,” he says.
A Center that Spans the Specialties
Like so many conditions that affect the CNS, the cumulative effects of MS relapses and progression cause symptoms to worsen over time. This makes early diagnosis and intervention crucial. It’s a fact that led Dr. Bar-Or and long-standing collaborator and friend Brenda Banwell, MD, Chief of the Division of Neurology at Children’s Hospital of Philadelphia (CHOP), to launch the CHOP-Penn Age-Span Program in MS and related disorders. This program aims to ensure a seamless transition of care from pediatric to adult care for individuals with MS and related disorders.
Through our age-span program we can follow individuals from day one with clinical, imaging and biological assessments to gain a better understanding of that individual’s biology and course,” explains Dr. Bar-Or. “This allows us to better educate and advocate for the best treatment on behalf of each person we see.”
While MS research and the Age-Span Program in MS and related disorders are at the heart of Penn’s CNET, they represent just a portion of its extensive and evolving work in the broader arena of neuroinflammation. “This field cuts across multiple disciplines at both Penn and CHOP and brings together people with different clinical and research interests and expertise,” Dr. Bar-Or says.
As proof, the center’s research interactions extend well beyond MS to include a range of other neurological conditions, psychiatric disorders, autoimmune conditions and cancer.
There are a lot of people already engaged in top-notch neuroinflammation research and many others who have joined as part of the NeuroInflammation Research Forum (NIRF), as the amazing potential across Penn’s diverse community is galvanized,” he shares. NIRF, which represents another outcropping of the center, now has over 100 members among Penn Medicine researchers and physicians and brings them together several times a year to hear from, and meet with, global leaders in the area of neuroinflammation.
A major attraction for NIRF members is to learn what one neuroinflammatory condition can teach them about another,” explains Dr. Bar-Or. “This has spurred us to think about the science of neuroinflammation collaboratively and emphasize the clinical and therapeutic opportunities that could be explored across specialty areas. It’s really incredibly exciting to think about the possibilities that lie before us as part of the ‘neuroimmune revolution’!”
