Progress in Treating Progressive MS
- Gary Birnbaum, MD
- Feb 22
- 6 min read
Anti-BCMA CAR-T therapy in patients
with progressive multiple sclerosis.
Qin, C., Dong, M-H, Zhou, L-H et al.
Cell 188, 6414–6423 e6411 (2025)
Introduction:
This is a very LONG blog. It deals with complex issues that I tried to put into context. The “Discussion” section at the end of the blog summarizes the issues and may be easier to digest.
For you brave ones, here are some of the issues:
1. There are many disease-modifying therapies (DMTs) for treatment of relapsing forms of multiple sclerosis. None are able to substantively affect the inflammation and degeneration that occurs within the central nervous system (CNS). Current data suggest that this compartmentalized or localized disease in the CNS is the main cause of chronic disease progression.
2. Immune cells called “B-cells” play a major role in MS. In addition to producing antibodies, B-cells produce inflammatory proteins called cytokines that activate cells in the peripheral immune system but also activate important populations of cells in the CNS. Reducing B-cells from the peripheral circulation with current anti-B cell DMTs reduces MS relapses. However, these DMTs cannot enter the CNS, and have no effect on the residual population of CNS-resident B-cells and the activation of brain cells that play a major role in perpetuating tissue destruction. This is best illustrated by the observation that while anti-B-cell antibodies effectively treat relapses in MS, they have little effect on progression independent of relapse activity (PIRA).
3. A category of CNS cells involved in chronic brain inflammation is microglia. They play a major role in maintaining brain health and have multiple complex functions. They clear debris in the central nervous system, and prune and maintain nerve cell connections. They also have immunologic properties, with the capacity to present antigens to T-cells and to secrete cytokines that induce inflammation and tissue destruction in the slowly expanding, chronic lesions characteristic of progressive MS.
4. Genetic engineering now makes it possible to alter the immunologic properties of T-cells. Specifically, it is now possible to change antigen receptors on the surfaces of T-cells so that the cells react only to specified proteins. Such altered cells are called “chimeric antigen receptor T-cells” or “CAR T-cells”. They have been used with great success in treating various blood cancers and are also being studied as treatments for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis, and relapsing MS. I posted a blog discussing the pros and cons of such therapies in MS on June 13, 2024.
5. Previous studies of CAR T-cells in MS used cells that reacted to the B-cell surface protein CD-19. Such CAR-T cells eliminated only a portion of an individual’s B-cells and left intact a population of mature B-cells called plasma cells. Plasma cells are the primary source of antibodies in the immune system. They also produce inflammatory cytokines. The paper that is the subject of this blog used CAR T-cells engineered to respond to a B-cell protein called “B-cell maturation antigen” or BCMA. This protein is expressed on plasma cells. The results of a Phase 1 trial testing the effectiveness of anti-BCMA CAR-T cells in persons with progressive MS is the subject of this paper.
Key Points:
1. The paper’s authors enrolled five individuals, four males and one female, with treatment-unresponsive progressive MS. One had primary progressive multiple sclerosis. The other four had secondary progressive MS. The study was a Phase 1 clinical trial. Phase 1 trials are meant to determine the dosage, frequency of administration, and most importantly, the safety of a potential new therapy. Effectiveness of therapy is not a primary goal of a Phase 1 trial. The trial involved administering autologous or self-CAR-T cells genetically engineered to respond to BCMA.
2. Age of the participants ranged from 36 to 55 years, with an disease duration of 3.4 to 25 years. All participants had significant disabilities, with EDSS scores ranging from EDSS 6 (needing unilateral support to walk) to EDSS 7 (unable to walk and needing to use a wheelchair).
3. All study subjects had received steroids in the past and three of the five had been given anti-CD20 monoclonal antibodies. All disease-modifying therapies were stopped prior to harvesting of T-cells for modification.
4. Prior to CAR-T cell infusion residual immune cells were chemically depleted with drugs (fludarabine and cyclophosphamide). This was followed by infusion of 1 million anti-BMAC CAR-T cells per kilogram of body weight.
5. The CAR-T cells rapidly expanded in blood, bone-marrow, and most importantly, in spinal fluid of all participants, depleting most B-cells, and importantly, most plasma cells.
6. In four subjects this cell death was associated with the release of large amounts of inflammatory cytokines, resulting in “cytokine release syndrome” or CRS. Symptoms of CRS are fever, low blood pressure, rapid heart rate, and if severe, organ failure and death. Fortunately, CRS in the study participants was very mild.
7. Most unexpectedly, all five patients improved over the next 9 months using several clinical parameters. 25-foot timed walking improved as did eye-hand coordination (“nine-hole peg test”). No new brain lesions were noted on MRIs, with a decrease in brain lesion volumes in two persons.
8. As numbers of CAR-T cells increased in the blood and spinal fluids of the participants over the next several weeks, spinal fluid levels of a marker of nerve cell death, neurofilament light chains, decreased in four individuals, with partial resolution of oligoclonal bands and decreased antibody levels in the spinal fluid.
9. As noted previously, microglia and macrophages play in important role in perpetuating CNS inflammation and tissue destruction in progressive MS, additionally stimulated by activated brain-residing B cells. To determine whether administration of anti-BCMA CAR-T cells affected microglia the paper’s authors studied spinal fluid markers of microglial inflammation. These were markedly reduced after infusion of CAR-T cells, as were levels of inflammatory cytokines.
10. They then measured numbers of microglia in the brain by administering a radioactive microglial marker and using magnetic resonance-positron emission tomography (MR-PET) scanning. Numbers of microglia were greatly reduced in three of the five study participant’ brains following anti-BCMA-CAR-T cell infusions.
11. Numbers of CAR-T cells gradually decreased over several months, but much more slowly in CSF, and most were gone by 6 months following infusion.
Discussion:
The importance of this paper is that it presents, for the first time, a means of treating the localized, compartmentalized inflammation that is the hallmark of progressive multiple sclerosis, a treatment that improved the clinical status of the five individuals in this study. Other disease-modifying therapies, such as Bruton's tyrosine kinase inhibitors, have the ability to enter the central nervous system and potentially affect brain cells such as microglia and macrophages. While working well in experimental models of MS such as experimental autoimmune encephalomyelitis, none have shown as robust an effect on clinical parameters as noted in this paper.
There are, of course, multiple issues that must be addressed before infusions of anti-BCMA specific CAR-T cells are established as a treatment for progressive MS. First is the small numbers of persons (only 5) enrolled in the trial. Second, this was a Phase I trial, with short follow-up and no control group of persons who were started on different brain-accessible disease-modifying therapies. To definitively establish the efficacy of anti-BCMA CAR-T cells as a treatment for progressive MS a randomized Phase III trial is needed, with a control group treated with disease-modifying therapies FDA approved for progressive MS, such as ocrelizumab, cladribine, and siponimod, and with a much longer follow-up.
Finally is the issue of long-term CAR-T cell safety. This was addressed in my previous blog on the subject. Anti-BCMA CAR-T cells are used with great success in the treatment of blood malignancies, in particular multiple myeloma. However, significant safety issues emerged with the use these cells, including anti-BMAC-specific CAR-T cells. The occurrence of secondary malignancies and development of brain dysfunction in the form of a Parkinson-like syndrome, are especially worrisome. Of course, persons with treatment-resistant blood cancer, previously exposed to powerful immuno- and chemo- therapies may have different susceptibilities to CAR-T cell toxicity than persons with treatment resistant progressive MS, and this must be determined.
While the observations presented in this blog’s subject paper are preliminary, and much more research needs to be done, they represent a potentially major advance in the treatment of progressive multiple sclerosis. Even more potentially important, since changes noted in progressive multiple sclerosis are already present very early in relapsing MS, treatment of progressive disease may need to be instituted soon after diagnosis, with the potential to possibly even prevent the development of secondary progressive disease.
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