CAR T-Cell Therapy: The Next Paradigm in Multiple Sclerosis?

Chimeric antigen receptor (CAR) T– cell therapy is an emerging therapeutic strategy in multiple sclerosis (MS), though it currently remains investigational. Access is limited to participation in clinical trials conducted at specialized medical centers with expertise in neuroimmunology and cellular therapy, where neurologists can refer suitable candidates for comprehensive trial education and eligibility screening. If ongoing studies demonstrate favorable safety and efficacy profiles, CAR T-cell therapy may establish a novel treatment paradigm and become more broadly accessible for MS management in the future. Jeffrey A. Cohen, MD, professor, Department of Neurology, Cleveland Clinic, Cleveland, Ohio, explains the rationale behind this therapeutic strategy, as well as the early clinical findings and safety profile.What is the overall rationale for developing CAR T-cell therapy for MS, and which limitations of current disease-modifying treatments does it aim to address?Jeffrey A. Cohen, MDCAR T cells are engineered effector T cells that express a chimeric antigen receptor (CAR). The CAR includes an extracellular antigen-recognition domain, typically derived from a monoclonal antibody, that enables binding to a selected target antigen without requiring major histocompatibility complex (MHC) presentation. It also contains a hinge region, which connects the antigen-recognition domain to the remainder of the CAR; a transmembrane domain, which anchors the CAR in the cell membrane; and an intracellular activation domain, typically derived from the T-cell receptor, which initiates T-cell activation after antigen recognition.This construct enables non-MHC-restricted antigen recognition, activation, and directed killing of selected target cells by effector T cells. The migratory capacity of CAR T cells may allow deep depletion of target cells not only in the blood but also in tissues, including the central nervous system (CNS). Autologous CAR T cells — derived from a patient’s own T cells — directed against surface markers on B-cell-lineage cells have been used to treat several hematologic malignancies, in which they have demonstrated high efficacy. Several CD19-directed CAR T products are approved for B-cell-derived leukemias and lymphomas, and several B-cell maturation antigen (BCMA)-directed CAR T products are approved for multiple myeloma.Because B cells play a key role in the pathogenesis of autoimmune diseases, including MS, a number of approved and novel CAR T cell products are being tested in these disorders. The rationale for CAR T therapy in MS is that deep depletion of B-cell-lineage cells by CD19- or BCMA-directed CAR T cells, both in the periphery and potentially within the CNS, may attenuate ongoing inflammatory injury. This includes focal lesion activity that drives relapsing disease, as well as compartmentalized, nonresolving diffuse inflammation within the CNS that may contribute to progression. With reconstitution of the B-cell population, there may be an immune reset toward a more self-tolerant phenotype, leading to long-lasting efficacy and possibly eliminating the need for disease-modifying therapy (DMT).Autologous CAR T-cell therapy involves harvesting the patient’s T cells through leukapheresis; manufacturing the cells by introducing a CAR directed against the selected target antigen and expanding the modified cells in culture; administering a short course of lymphodepleting conditioning chemotherapy to improve engraftment; infusing the CAR T cells; and then monitoring the patient, providing supportive care, and managing adverse effects.CAR T technology is rapidly evolving beyond currently approved products. Some investigational CAR T products are allogeneic, meaning they are generated from a donor rather than from the individual patient. Allogeneic CAR T cells may be administered off the shelf and do not require T-cell harvesting by leukapheresis or individualized cell manufacturing. Adaptations to CAR design may allow recognition of a broad range of antigens and improved activation. In addition, in vivo generation of CAR T cells —generation within the recipient without laboratory-based cell manufacturing — is under study.How does CAR T therapy’s conceptual approach as a "cellular reset" differ fundamentally from standard MS DMTs focused on peripheral immune suppression?Elimination of circulating B cells by CAR T-cell therapy may have the potential to provide efficacy in relapsing MS that is at least comparable to, and possibly greater than, that of currently available DMTs. Depletion of B cells within the CNS may contribute to control of focal inflammatory activity in relapsing disease and may also be beneficial in slowing or reversing progression, for which currently available DMTs have limited benefit. With reconstitution of the B-cell population, there may be an immune reset that leads to long-lasting efficacy, possibly in the absence of ongoing DMT. Emerging results are encouraging, but substantially more experience is needed to determine whether these goals can be achieved.What are the key safety and efficacy findings so far from CAR T clinical trials in MS, and how should clinicians interpret these early data when counseling patients who ask about this option?To date, published experience with CAR T therapy in autoimmune diseases, including MS, is limited, although a sizable number of clinical trials are ongoing or planned. There are well-recognized potential early and delayed toxicities with CAR T therapy in the setting of hematologic malignancies. So far, experience in autoimmune diseases, including MS, has been reassuring, with seemingly lower rates of known toxicities.Efficacy data are also limited but encouraging. Clinicians should counsel patients that CAR T therapy for MS appears promising; however, the specific target population or populations, as well as its safety and efficacy relative to available DMTs, are not yet known with certainty. CD19- and BCMA-directed CAR T therapy is being tested in both treatment-refractory relapsing MS and progressive MS. Initial findings in both indications are encouraging but remain preliminary. As additional results are presented at scientific meetings and published, the role of CAR T therapy in MS will become clearer.What are the key safety concerns with CAR T therapy in MS, and how are patients in clinical trials monitored both in the immediate postinfusion period and in the longer term?We are still learning about the safety of CAR T therapy for MS and how it compares with the broader experience in hematologic malignancies and other autoimmune diseases. For autologous CAR T-cell therapy, leukapheresis and lymphodepleting chemotherapy are often delivered in the outpatient setting, although practice varies by protocol and treatment center. Because adverse effects are uncommon but can sometimes be severe, CAR T-cell administration and initial monitoring are typically performed during a 10- to 14-day hospitalization, followed by close outpatient monitoring for the subsequent 1-2 months.Early toxicities may include adverse effects associated with leukapheresis; adverse effects related to lymphodepleting chemotherapy, including nausea, vomiting, neutropenia, and neutropenic fever; and cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR T-cell administration. CRS may range from mild to severe and can manifest fever, fatigue, anorexia, headache, arthralgia, myalgia, nausea, dyspnea or hypoxia, hypotension, cytotoxic shock, and death. ICANS can also range from mild to severe and may include depressed level of consciousness, encephalopathy, seizures, neuropsychiatric or behavioral changes, aphasia, motor impairment, and cerebral edema. Other potential early toxicities include immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, characterized by fever and low blood counts, and local immune effector cell-associated toxicity syndrome, which may involve transient accentuation of symptoms in organs previously affected by the underlying autoimmune disease. Potential delayed toxicities include hypogammaglobulinemia; B-cell aplasia; immune effector cell-associated hematotoxicity, characterized by prolonged low blood counts; infection; and malignancy. In the setting of CAR T-cell therapy for MS, potential concerns for long-term risks, based largely on experience in hematologic malignancies, include second primary malignancies, such as rare CAR-positive T-cell malignancies, and delayed neurologic toxicities. Neurologic toxicities, reported predominantly with BCMA-directed CAR T-cell therapy for multiple myeloma, include myelitis, cranial nerve palsies, and movement and neurocognitive toxicity characterized by parkinsonism, cognitive impairment, and behavioral changes.Could CAR T cell therapy be used as an induction “immune reset” followed by maintenance with traditional MS agents, and how are researchers currently thinking about integrating it into long-term MS management?The current rationale for CAR T therapy in MS is that deep depletion of B-cell-lineage cells in the periphery, and potentially within the CNS, may have potent efficacy in reducing or eliminating ongoing inflammatory damage. This includes focal lesion activity that drives relapsing disease, as well as potentially compartmentalized, nonresolving diffuse inflammation that may contribute to progression.With reconstitution of the B-cell population, there may be an immune reset that leads to long-lasting efficacy, possibly without the need for ongoing DMT. Emerging results are encouraging, but substantially more experience is needed to determine whether these goals can be achieved. At present, the efficacy and safety of CAR T therapy in relapsing and progressive MS, compared with available DMTs, remain uncertain.Editor’s Note: This article was created using several editorial tools, including generative AI models, as part of the process. Human review and editing of this content were performed prior to publication.