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  • Writer's pictureGary Birnbaum, MD

CAR-T cells-A new treatment for MS? Or maybe not.

Updated: Jun 17

A CAR-T therapy for multiple sclerosis enters US trials for first time

Asher Mullard

Nature, 22 February 2024


CAR-T cells, multiple sclerosis
AI-drawn representation of CAR-T cells

Bottom Line:

Chimeric antigen receptor T cells or CAR-T cells are genetically altered immune cells that are an FDA approved treatment for certain potentially fatal blood cancers and lymphomas. CAR-T cells also have been used to treat several autoimmune diseases. A small, two person safety trial of CAR-T cells was just published with encouraging results. A larger clinical trial to determine if CAR-T cells are of benefit to persons with relapsing forms of multiple sclerosis (MS) is now starting. Will CAR-T cells be an important addition to the already large number of treatment options for persons with relapsing forms of multiple sclerosis and possibly progressive multiple sclerosis? The answer is not known, but potential issues with CAR-T cells should be discussed, both in terms of possible benefits and toxicities. Some of these are discussed below.

The rationale for the use of CAR-T cells in MS is based on the observation that an activated immune system is responsible for much of the tissue damage in MS. The majority of disease-modifying therapies for the treatment of MS affect the immune system. Some of the most effective are monoclonal antibodies that deplete populations of immune cells called B cells. This observation established that B cells play an important role in the MS disease process. If removing B cells from the blood of persons with MS is beneficial, are there better, safer and less costly ways than monoclonal antibodies of achieving such depletion? Chimeric antigen receptor T cells (CAR-T cells) may be such a method, but important issues need to be resolved in terms of efficacy, safety and risk:benefit ratios before widespread usage of CAR-T cells can be advised. These are discussed below.

 

Key Points:

1.        T cells are major cells of the immune system and have multiple functions. These include turning on or activating B cells, releasing inflammatory proteins called cytokines, and killing cells.

2.        T cells have on their surfaces proteins called receptors that bind to other proteins called antigens. Binding of a T cell receptor to an antigen results in that T cell becoming activated.  If the T cell is a “killer” or cytotoxic T cell, and the antigen it binds to is on the surface of a cell, it will kill the cell.

3.        Using tools of molecular biology it is possible to remove the receptors on the surfaces of T cells and replace them with different or chimeric receptors. This results in chimeric antigen receptor T cells or CAR-T cells.

4.        Making CAR-T cells is a costly and lengthy process. Purified T cells are obtained by taking blood from the person to be treated (autologous cells). This process is called "lymphopheresis." Cells are then injected with a virus containing the genetic instructions needed to produce the desired chimeric antigen receptor. This process is called “transfection” or "transduction." Viral DNA is released in the infected T cells, the chimeric antigen receptor is produced by the cells and the cells are then grown in tissue culture until sufficient numbers of are present to treat. This can take weeks.



5.        CAR-T cells have been used in the treatment of B cell leukemias and lymphomas with great success. If CAR-T cells were to be used for the treatment of MS, the replacement receptor would be one that binds to a protein found predominantly on the surfaces of mature B cells. One such protein is CD20, the same protein that the monoclonal antibodies used to treat relapsing forms of multiple sclerosis recognize. Binding of these monoclonal antibodies to B cells results in their depletion from the circulation..

6.        CAR-T cell binding to CD20 also should result in killing all or most of the B cells that express this protein, similar to the result seen with monoclonal antibodies. However, there are at least three main questions regarding the use of CAR-T cells in MS that need to be answered.



7.        Would using CAR-T cells instead of monoclonal antibodies result in a more efficient and complete removal of B cells? Probably.

·      Monoclonal antibodies need to be administered periodically to maintain low B cell numbers. Studies of CAR-T cells in persons with cancer have shown long term survival for up to decades, with cancer remission. However, this may not be the case in persons with MS since when CAR-T cells were used to treat persons with other autoimmune diseases, B cells gradually reappeared.

·      Only 0.1% of circulating monoclonal antibodies are able to enter the central nervous. CAR-T cells have that capability, resulting in removal of B cells within the central nervous system and lowering of CSF antibody levels.

·      CAR-T cells can be made that have two or more different chimeric receptors of different specificities attached to their surfaces, allowing them to interact with more than one protein antigen. This raises the possibility of removing B cell populations more specific to MS pathogenesis, such as B cells making antibodies to myelin oligodendrocyte glycoprotein (MOG) or Epstein-Barr virus, both implicated in the pathogenesis of MS.

·      CAR-T cells have recently been used to treat autoimmune diseases such as systemic lupus erythematosis, myositis, and systemic sclerosis with beneficial results, albeit using CAR-T cells designed to interact with a protein other than CD20. Of note is that CAR-T cells did not persist in these individuals and responses to some vaccines remained, even in the absence of B cells. Also, after 3-4 months, B cells gradually reappeared.

8.        Would using CAR-T cells be safer than using monoclonal antibodies? NO!

·      The persistence of CAR-T cells, with possible continued long-term removal of B cells, could jeopardize the normal functions of a person’s immune system, resulting in lowered levels of antibodies and an increased risk of infection. Persistence of CAR-T cells was not noted with a different population of CAR-T cells used to treat autoimmune diseases, but this could be an issue with anti-CD20 CAR-T cells used to treat MS.

·      CAR-T cells may cause cardiac toxicity, usually due to the release of large amounts of immunologically active proteins called cytokines. Such a release may result in a “cytokine storm.” High levels of cytokine in the blood can be toxic and even fatal.

·      Infusion of CAR-T cells can cause toxic injury to the central nervous system (neurotoxicity), with varying degrees of severity. While mild cases of neurotoxicity recover, severe cases have been fatal and treatment of this condition remains uncertain.

·      Treatment with CAR-T cells in persons with blood malignancies increases their risk of developing an unrelated cancer. The risks are small, and the benefits to persons with potentially fatal cancers are felt by the FDA to outweigh the risks. Nevertheless, the FDA now requires this warning to be added to all approved CAR-T cell therapies. In regards to persons with MS, the risks are not known, but Epstein-Barr virus infection is associated with the onset of MS and with an increased risk of T cell and B cell malignancies. The risk could possibly increase in a setting of immune suppression, as occurs with B cell depletion, the intended effect of CAR-T cell treatment.

9.        Is CAR-T cell therapy less costly than anti-B cell monoclonal antibody therapy?. Possibly.

·      The annual list prices for FDA-approved anti-B cell antibodies for treatment of relapsing forms of multiple sclerosis are $59,000 for Ublituximab, $78,858 for ocrelizumab and $83,000 for ofatumumab. Actual costs will vary with different insurances and in different countries (e.g. less in Canada and more in the USA). Rituximab is an older, effective B cell depleting antibody, but not FDA approved for treatment of relapsing forms of multiple sclerosis. The annual cost of this equally effective older drug when used off-label to treat relapsing forms of multiple sclerosis is $5,399.28.

·      Commercial CAR-T cells prepared in the United States currently cost between $370,000 and $530,000, not including hospital fees and drugs to treat side effects. The cost of CAR-T cells produced in India is between $30,000 and $40,000 per treatment.

·      As noted above, CAR-T cells are costly due to a lengthy production process (see Key Point #4). Much research is being done to reduce the costs of preparing CAR-T cells and the time needed to prepare the cells. Some of the studies involve using T cells from unrelated donors (allogeneic cells), removing cell proteins that could cause harm to the immunologically “foreign” recipient, transfecting them with viral DNA specific for the desired receptor, expanding their number, and storing them. This would allow rapid “off the shelf” treatment with CAR-T cells.

·      Researchers are also studying whether CAR-T cells can be produced by transfecting an individual’s T cells with an intravenous (IV) infusion of chimeric receptor DNA encased in a lipid membrane. If successful, this would eliminate the need for T cell harvesting, external or ex-vivo viral transfection and prolonged cell culture, greatly lowering production costs.



Discussion:

CAR-T cells are a powerful tool for removing “undesirable” cells from an individual’s blood stream and central nervous system, and possibly also from solid organs. The ability to design CAR-T cells’ chimeric receptors to recognize more than one target makes removal of cells specific to a particular disease feasible. As we learn more about the illness, this could be especially valuable in treating persons with MS. While the cause of MS remains unknown, certain viruses, in particular Epstein-Barr virus, have been implicated in the disease process, and removing Epstein-Barr virus reactive cells with CAR-T cells could be beneficial, both in terms of the MS disease proces but also potentially reeducingthe risk of developing a malignancy. In addition, antibodies to myelin oligodendrocyte glycoprotein (MOG) appear to have a role in causing an MS-like illness, and using CAR-T cells to deplete B cells producing such antibodies may be beneficial, though one study of an animal model of MS (experimental autoimmune encephalomyelitis) showed worsening with removal of anti-myelin oligodendrocyte glycoprotein producing B cells using CAR-T cells.

As with many powerful treatments there are substantive potential side effects, as outlined above. Most disquietingly is the potential for central nervous system toxicity, with possible worsening of MS. The clinical trials being initiated will provide some insights into whether use of CAR-T cells has an acceptable risk:benefit ratio but given the relative rarity of some of the reactions, such as appearance of new cancers, large numbers of persons will need to be treated to fully assess the safety of this therapy for a chronic, non-fatal illness. Given the relative safety of most of the high-efficacy disease-modifying therapies currently available, use of these agents most likely will continue, at least until more data are available.

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