News commentary
One particular session on Day 2 of the four-day 7th Joint ECTRIMS-ACTRIMS Meeting — which drew 10,000 researchers, doctors, industry representatives, and patient advocates to hear about advances in multiple sclerosis (MS) treatment and understanding — attracted so much interest that all seats were taken in the huge lecture hall and late-comers had to claim spots along the walls.
This event was the Burning Debate session, called “Rumble in the jungle: B cells vs. T cells” — an allusion to the historical boxing match between George Foreman and Muhammad Ali in 1974.
At ECTRIMS, the duel pitted two world authorities on MS, with distinct views on the importance of T-cells and B-cells in the disease, against one another. But like almost everything in MS, reality intruded; the complexity of this disease made a clear-cut face-off impossible.
Rather, the fierce debate suggested by the title turned out to be more of an affirmative pat on the back as each researcher made his respective arguments, with only a slight disagreement on the relative importance of the two cell types evident between the two men.
Stephen Hauser with the University of California, San Francisco, a neuroimmunologist who has contributed vastly to the understanding of MS disease mechanisms, argued that B-cells are, indeed, most important in MS. But he showcased data supporting T-cell involvement as well.
And while David A. Hafler — an immunologist at Yale School of Medicine who has provided equally important contributions to the understanding of how the disease develops — did not disregard B-cells, he argued that T-cells cannot be ignored.
Hauser, who spent decades on the development of a B-cell therapy, including Ocrevus (ocrelizumab), opened the discussion by simply showing data from the two Phase 3 trials exploring that now-approved treatment in relapsing MS patients.
“This is my argument,” he said, with the backdrop of a graph showing how Ocrevus reduced inflammatory lesions by 95% to 97% compared to interferon-beta 1a in the studies exploring the drug in those MS patients.
Unlike the majority of T-cell-focused MS treatments on the market, Ocrevus targets B-cells. And trials did show that it produced results unequaled to those seen in other studies, both in lowering magnetic resonance imaging (MRI) lesions and in controlling signs of the disease, Hauser said.
While the effects in primary progressive patients were not as pronounced, it was the first time researchers actually saw a treatment effect in this population, suggesting that “the doors are jarred” in terms of understanding progressive disease processes — with the help of insights based on a B-cell treatment.
The importance of B-cells in MS is also supported by the demonstrated fact that once B-cells return after treatment with a B-cell-depleting drug, disease activity remains low, Hauser said. This, he thought, suggests that the immune system is somehow reset — no longer attacking the body — by the very act of a treatment having depleted B-cells.
B-cells are also impacting T-cell processes, Hauser continued, noting that the depletion of CD20-type B-cells also reduces T-cells thought to be involved in MS.
The opposite is also true. T-cell-focused therapies, including interferon and glatiramer acetate, impact the behavior of B-cells even if they were not designed to do so. For instance, such drugs alter how B-cells mature, become activated, and modulate immune processes.
Although previous data suggests that T-cells are also involved in disease processes, B-cells outnumber T-cells in MS lesions, Hauser said, suggesting they are likely more important.
“B-cells and T-cells are inseparable allies — they cannot exist apart — and in MS, they are partners in crime. But B-cells are the ringleader,” Hauser concluded.
Hafler, on his part, agreed to some degree. “MS is not a B-cell disease,” he said. “MS is not a T-cell disease. MS is an immune disease with involvement of the whole adaptive and innate systems.”
“How can you not say B-cells are important with the Ocrevus data, but what role do B-cells have in inducing disease?” he asked rhetorically.
So-called genome-wide association studies suggest that both B- and T-cells genes are involved in MS risk. And studies of myelin-reactive T-cells do show abnormalities in MS patients.
In healthy people, myelin-reactive T-cells mainly secrete the anti-inflammatory factor interleukin 10. But in those with MS these cells take on a more pro-inflammatory profile, also secreting factors such as interleukin 17 and interferon-gamma, Hafler said. Such data suggest T-cells may be involved in initiating disease processes.
But these T-cells lose some of their inflammatory features when B-cells are depleted, he added, again endorsing the view that both cells can be villains in MS.
To underscore his position in the debate, Hafler spent a large part of his talk addressing the molecular characteristics of T-cells in MS. There is, he said, a high frequency of autoreactive T-cells in the spinal fluid, and these cells appear to have features not seen in healthy people.
Disease-specific features, however, are not limited to T-cells. B-cells also show alterations when those of healthy people are compared to patients with MS, particularly in their activation state, Hafler said.
So, with the boxing reference in mind, most people might agree that the duelers in this debate were, in fact, fighting for the same team — a rather reassuring notion for everyone touched by MS and eager to see research moving forward.
