Cell-Based Therapies Show Potential to Promote Repair in Multiple Sclerosis
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by
Ree Webster
Cell-based therapies—namely stem cell transplantation, chimeric antigen receptor (CAR) T-cell therapy, and regulatory T-cell transplantation—offer an especially promising yet relatively untapped approach to treating multiple sclerosis (MS). Jeffrey A. Cohen, MD, director of the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research in Ohio, is one of the many excited about these new possibilities. Dr. Cohen, when speaking to the Consortium of Multiple Sclerosis Centers (CMSC) meeting, noted that over 20 disease-modifying therapies (DMTs) and a broad range of options are now available for treating MS.
“But there are some patients with very active disease—primarily in people with lesion activity—and none of the available therapies promote repair…
“Our hope is that cell-based therapies may fill some of those needs. One need would be to provide more effective control of disease activity, relapses, and MRI lesion activity. The other hope is that cell-based therapies might promote repair, which none of our current medications does.”
Advantages and Risks of Stem Cell Therapy
Stem cell therapy offers significant advantages over many other types of treatment, mainly due to the procedure utilizing the patients own stem cells, which reduces the risk of infection and rejection. Unlike traditional therapies, stem cells can transform into various cell types, enabling the repair of various different damaged tissues and organs. In addition, stem cell treatments reduce the need for invasive surgeries and long-term medication, which both help to minimize recovery time as well as potential side effects.
Some of the main benefits of stem cell therapy include:
- Promotes Natural Healing and Regeneration: Stem cells can develop into specialized cell types, aiding in the repair and regeneration of damaged tissues and organs.
- Minimizes Invasive Procedures: Stem cell therapy can reduce or eliminate the need for surgery, offering a less invasive treatment option with shorter recovery times.
- Reduces Dependency on Medications: By addressing underlying damage, stem cell therapy may decrease the need for long-term medications and their associated side effects.
- Helps Treat a Range of Conditions: It has shown potential in treating heart disease, autoimmune disorders, neurodegenerative diseases, and joint injuries.
- Improves Quality of Life: Patients often experience enhanced mobility, reduced pain, and overall improvements in daily functioning after stem cell treatments.
- Encourages Personalized Treatment: Stem cell therapy can be tailored to individual needs, promoting a more targeted and effective approach to healing.
However, these benefits come at a cost, as there still exists several risks when performing certain stem cell therapies. For example, when performing hematopoietic stem cell therapy (HSCT), high doses of chemotherapy are utilized to deplete the immune system, which then gradually rebuilds over several years; resulting in a more normal phenotype. Dr. Cohen explained:
“A few studies show that it has dramatic efficacy. But one of the caveats is there’s really been only 1 randomized trial…
“The other issue is that it’s a very complicated, quite risky procedure, although the rate of transplant-related mortality has gone down. Most patients have some serious adverse events.”
These applies to both the direct and indirect side effects of the chemotherapy such as infection or bleeding until the bone marrow is repaired. Dr. Cohen added:
“We know that the nervous system, like all tissues in the body, attempts to repair itself after damage, including from abnormal inflammation in multiple sclerosis, but in many patients, that repair is inadequate. A number of cell-based approaches are under evaluation to hopefully augment the natural repair processes…
“In the case of the repair-promoting strategies, the main potential complications relate to the cells themselves. The intent after transplantation is for them to traffic to the nervous system, and to stimulate repair—either by repairing the damage directly, or by augmenting the naturally occurring repair mechanism by other cells…
“There’s always the potential that those cells may go haywire. They may, instead of having beneficial effects, may themselves turn into tumor cells.”
Most Effective Approaches for Treating Patients With SPMS
Whilst researchers have conducted several uncontrolled studies on stem cell therapy in MS, which have generated lots of interest, there has only been 1 randomized trial of HSCT in MS, Dr. Cohen noted:
“It’s a complicated procedure. Not every institution has both sophistication in hematopoietic stem cell transplantation and management of MS. You need both of those to do a study…
“Some people are already convinced that it works…
“They don’t feel the need for an additional study. Others feel that it’s too dangerous, and that with our available disease-modifying therapies, it’s unnecessary. Our experience has been that there still are quite a few people with MS for whom it’s warranted.”
One of the pioneers in the field is Greek neurologist Dimitrios Karussis, MD, PhD, head of the Multiple Sclerosis Center at Hadassah University Hospital in Jerusalem, Israel. Dr. Karussis is currently planning a phase 2b trial including 80 patients each with secondary progressive MS (SPMS) treated with stem cells taken from their own bone marrow.
In a previous double-blind phase 2 study of 48 patients with SPMS, Dr. Karussis reported a “pronounced beneficial effect” among those receiving stem cells into the cerebrospinal fluid; their disease not only stabilized but the patients improved in motor and other functions.
Cohen attributed results to 3 factors: cells’ adaption of neurotrophic properties which makes them better able to support repair mechanisms; intrathecal administration via spinal tap, and multiple administrations:
“His work has primarily been on mesenchymal stem cell transplantation. That is one of the strategies in repair-promoting mechanisms, and he’s reported very dramatic results…
“Dr. Karussis’s most recent studies have incorporated all 3 of those factors, and that may explain some of the good results he’s gotten,”
Dawn of CAR-T cell therapy in autoimmune diseases
New CAR-T Therapy for MS
Panayiota Petrou, MD, also of the Multiple Sclerosis Center, noted that HSCT has been used in small clinical trials of patients with MS with very good results:
“But this procedure has many possible complications and very high mortality…
“It has improved in recent years since the protocol has changed, but it is still not routine. HSCT needs immunosuppression. It is relevant and indicated in patients with very active disease, and at Hadassah we do have experience with this procedure and were one of the first to work on it with animal models and patients.”
Mesenchymal stem cell transplantation is a procedure that does not need any immunosuppression and has almost no side effects. Petrou explained that the treatment targets progressive MS patients, since here the idea is neurogeneration.
CAR-T cell therapy, which Dr. Cohen describes as “the new kid on the block” when it comes to MS, has revolutionized the treatment of cancer, especially lymphomas and leukemias. The rationale for this, he said, is that some CAR-T products already approved by the US Food & Drug Administration could be relevant to autoimmune diseases such as MS.
“Secondly, CAR-T cells produce a very deep depletion of B cells not only in the blood—like the currently approved monoclonal antibodies—but also within the tissues, including the central nervous system,” he said. “It’s anticipated that that may lead to better efficacy, particularly not only in relapsing MS, but possibly and hopefully in progressive MS.”
The chemotherapy required for CAR-T therapy before reinfusion of T cells typically involves cyclophosphamide and fludarabine, and these are considered much less damaging than the procedure required for stem cell transplant. Nevertheless, adverse effects are stll possible with this method of treatment, either from administering therapy itself, or from the chronic depletion of B cells.
“There can be infusion reactions related primarily to the dose, and also the amount of target. Both those complications have been seen—not infrequently in cancer—but it remains to be seen whether they occur in MS patients who we expect will get a lower dose, and the target burden is not as dramatic,” he said.
With regard to the chronic depletion of B cells, in fact, “CAR-T cells may be too effective, and lead to some predisposition to infection,” Dr. Cohen added. “Again, that remains to be seen.”
