Chimeric antigen receptor (CAR) T-cell therapy: A new horizon for neurologic immune-mediated diseases

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Author: Joaquin A Pena MD

Introduction

Neurologic immune-mediated diseases, such as multiple sclerosis and neuromyelitis optica spectrum disorder, are debilitating conditions with a wide range of clinical and pathological features, often involving B cells as a central component. Despite progress in “high efficacy” disease-modifying therapies, some patients still experience ongoing disease activity and progression, leading to increasing disability and substantial personal and societal costs. Current treatments often need to be administered long-term, which poses risks of accumulated immunosuppressive and off-target side effects, without fully controlling the disease. The goal for future therapies is to "reset" the immune system to a lasting immunotolerant state, ideally eliminating the need for continuous immunosuppression.

Chimeric antigen receptor T-cell therapy, a revolutionary treatment for B-cell and other hematological malignancies, has demonstrated the capacity for long-term remission in otherwise refractory cancers. Its emerging application in autoimmune diseases, including neurologic immune-mediated diseases, presents a promising, more selective immunoablative approach that could offer increased efficacy and potentially fewer adverse events than intensive chemotherapy-based treatments, such as autologous hematopoietic stem cell transplant.

Mechanism of action: reprogramming the immune system

CAR T cells are genetically engineered immune effector cells, predominantly T cells, that express a synthetic transmembrane protein called a chimeric antigen receptor. This receptor enables the T cell to recognize and eliminate cells expressing a specific target antigen.

The process begins with collecting a patient’s T cells through leukapheresis, followed by their enrichment, activation, and genetic modification using a viral vector to express the chimeric antigen receptor. These CAR T cells are subsequently expanded to millions of cells. The chimeric antigen receptor’s structure generally includes an extracellular antigen-recognition component (often a single-chain variable fragment), a transmembrane region, an intracytoplasmic costimulatory domain (such as 4-1BB or CD28), and a CD3 intracellular signaling domain.

Before CAR T-cell infusion, patients undergo a short course of lymphodepleting chemotherapy (usually fludarabine/cyclophosphamide). This crucial step not only helps decrease disease burden in cancer but also creates a supportive microenvironment for CAR T cells to expand and survive effectively in vivo.

In neurologic immune-mediated diseases, CAR T-cell therapy often targets B cells, which are known to promote disease through antigen presentation, proinflammatory cytokine production, and even residency within the central nervous system in conditions like multiple sclerosis. Pathogenic antibodies found in diseases such as myasthenia gravis (acetylcholine receptor or MuSK antibodies) and neuromyelitis optica spectrum disorder (aquaporin-4 immunoglobulin G) are also B-cell-mediated. Anti-CD19 CAR T cells, which target an antigen shared by nearly all B cells, exemplify this targeted approach. A significant advantage of CAR T cells over traditional monoclonal antibodies is their ability to penetrate tissues, including the CNS, accessing sites such as deep lymph nodes and the spleen, and potentially eliminating pathogenic B cells and plasmablasts that are difficult for systemic therapies to target. Unlike antibody-mediated depletion, CAR T cells operate autonomously, not requiring accessory cells, such as NK cells or macrophages, to exert their cytotoxic effects.

Clinical efficacy in neurologic immune-mediated diseases

Early-phase trials in B-cell-driven autoimmune conditions have demonstrated dramatic clinical responses with favorable safety profiles.

• Neuromyelitis optica spectrum disorder. Interim results from a phase 1 trial (NCT04561557) involving 12 refractory patients with neuromyelitis optica spectrum disorder who were treated with autologous BCMA CAR T-cell therapy showed universal clinical improvement. At a median follow-up of 5.5 months, 11 of 12 patients achieved remission (relapse-free and off immunosuppression), with AQP4-IgG antibody reversal seen in 70% of patients. One patient experienced a relapse at 14 months, correlating with an increase in AQP4-IgG levels.
• Multiple sclerosis. Preclinical studies in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis have shown promising results with CAR T cells targeting myelin basic protein and myelin oligodendrocyte glycoprotein, leading to sustained treatment effects. Anti-CD19 CAR T cells in experimental autoimmune encephalomyelitis models significantly reduced disease scores, delayed onset, and maintained depletion of CD19+ B cells for over 25 weeks, outperforming CD20 antibodies. In humans, two patients with progressive multiple sclerosis (one secondary progressive, one primary progressive) were treated with a single dose of autologous CD19 CAR T cells (KYV-101). Both had experienced progression despite ocrelizumab. Importantly, CAR T cells were detected and expanded in both the blood and cerebrospinal fluid without clinical signs of neurotoxicity. In the patient with secondary progressive multiple sclerosis, intrathecal antibody production (oligoclonal bands) was notably reduced, decreasing from 13 to 6 bands, suggesting an effect on CNS-resident B cells. Although one patient developed a new spinal cord lesion 2 months after treatment, its cause remains unclear. Several international clinical trials, including those targeting CD19 in nonrelapsing, progressive multiple sclerosis (NCT06138132) and tandem CD20/BCMA in relapsing-remitting multiple sclerosis (NCT06249438), are currently underway to further evaluate this approach.

These initial findings suggest that CAR T-cell therapy, particularly B-cell-targeted constructs, has the potential to achieve long-term, potentially permanent remission and eliminate the need for ongoing immunosuppression in neurologic immune-mediated diseases.

Adverse events and their management

CAR T-cell therapy has a distinct toxicity profile, with the most notable acute adverse events being cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.

• Cytokine release syndrome. An acute systemic inflammatory response marked by fever and possible multiorgan failure, including low blood pressure and lack of oxygen. Although its occurrence can be high (37% to 93% in cancer trials), severe (Grade 3 to 4) cases are less frequent (1% to 23%). Treatment is well-established, mainly involving tocilizumab (an anti-interleukin-6 receptor antibody) and corticosteroids.
• Immune effector cell-associated neurotoxicity syndrome. This neurotoxicity typically manifests days to weeks after infusion (4 to 10 days). Symptoms range from confusion, aphasia, handwriting changes, and tremor to more severe presentations like seizures and cerebral edema. Treatment relies on dexamethasone or high-dose methylprednisolone. The incidence varies (15% to 30%), with severe cases generally occurring at a rate of less than 20%. Importantly, in the reported multiple sclerosis cases, no immune effector cell-associated neurotoxicity syndrome was observed despite the presence of CAR T cells in the CSF. The lower target antigen burden in autoimmune diseases compared to hematological malignancies is hypothesized to contribute to a reduced incidence and severity of these inflammatory toxicities.
• Hematotoxicity. Prolonged cytopenia (eg, neutropenia, anemia, thrombocytopenia) is common. Early onset is often linked to lymphodepleting chemotherapy, whereas late onset may be associated with previous intensive treatments and severe cytokine release syndrome. Management includes supportive care, growth factors, and intravenous immunoglobulin.
• Hypogammaglobulinemia and infections. B-cell aplasia and resulting hypogammaglobulinemia are common after anti-CD19 CAR T-cell therapy, which increases the risk of infections. Prophylactic intravenous immunoglobulin is often advised. Additionally, prophylactic antimicrobials for specific pathogens (eg, herpes simplex virus, varicella-zoster virus, Pneumocystis jirovecii) are also recommended.
• "On-target, off-tumor" toxicity. A vital consideration is that CAR T cells might harm normal tissues that express the target antigen. For example, anti-BCMA CAR T-cell therapies in blood cancers have been linked to Parkinsonism, cranial nerve palsies, and peripheral neuropathy, some of which could be irreversible due to BCMA expression in neural tissue. The safety of BCMA-targeted CAR T cells for neurologic immune-mediated diseases needs a thorough assessment.

Comparisons with existing treatments

• Disease-modifying therapies. Although monoclonal antibodies (eg, anti-CD20 ocrelizumab, anti-CD19 inebilizumab) have improved outcomes, they are not curative, require long-term use, and may not effectively access CNS compartments where disease activity continues. CAR T-cell therapy offers the possibility of a one-time treatment that could lead to lasting remission, potentially freeing patients from the need for chronic immunosuppression.
• Autologous hematopoietic stem cell transplant. An effective treatment for highly active or refractory neurologic immune-mediated diseases, autologous hematopoietic stem cell transplant involves aggressive chemotherapy to eliminate and rebuild the immune system. However, it is an intensive procedure associated with significant short- and long-term side effects, including a higher, yet reduced, risk of treatment-related mortality, infections, infertility, and secondary autoimmune diseases or cancers. CAR T-cell therapy is being studied as a more targeted immunoablative option with potentially fewer adverse events and similar or better efficacy.

Guidelines and recommendations

Current guidelines from organizations like the European Society for Blood and Marrow Transplantation offer recommendations on patient selection for innovative cellular therapies, including CAR T cells. For cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, established protocols suggest prompt supportive care, anti-cytokine treatments (such as tocilizumab for cytokine release syndrome), and corticosteroids (for immune effector cell-associated neurotoxicity syndrome). Close clinical and immunologic monitoring is crucial after infusion, with neurologic assessments and possibly advanced imaging (eg, MRI) and EEG to identify and manage toxicities. Prophylactic intravenous immunoglobulin is recommended for hypogammaglobulinemia, and specific anti-infective prophylaxis protocols are implemented.

Ongoing controversies and unresolved debates

• Predicting and mitigating toxicity. Although lower target antigen burden in autoimmune diseases indicates reduced toxicity, more research is necessary to improve risk stratification and management strategies, particularly for patients with pre-existing CNS inflammation, who are already at increased risk for neurotoxicity.
• Optimal chimeric antigen receptor design and target selection. The ongoing discussion focuses on the best chimeric antigen receptor design (eg, CD28 versus 4-1BB costimulatory domains) for different neurologic immune-mediated diseases, aiming to balance effectiveness with toxicity. The ability of chimeric autoantibody receptor (CAR) T cells to specifically target autoantibody-producing B cells, rather than eliminating all B cells, presents a more precise strategy with potentially less overall immunosuppression and lower risk of impairing protective antibody levels.
• Long-term immunologic impact. The lasting effects of B-cell depletion on immune reconstitution, protective humoral immunity, and the risk of late adverse events such as secondary malignancies remain important areas for research. Although experts believe the benefits of CAR T-cell therapy outweigh these rare risks, lifelong monitoring is advised.
• Dual immunosuppression. Managing concurrent immunosuppressive therapies that impact T cells in patients receiving B-cell targeted CAR T cells requires careful planning, including appropriate washout periods, to prevent excessive immunosuppression and reduce infection risk.

Future directions and research gaps

Initial experiences with CAR T-cell therapy in neurologic immune-mediated diseases are promising. However, larger, well-designed clinical trials with extended follow-up periods are needed to conclusively determine the long-term safety and efficacy and the best patient populations. Research efforts are focused on:

• Optimizing chimeric antigen receptor constructs to improve specificity and minimize off-target effects and toxicity.
• Developing allogeneic CAR T-cell therapies to address the logistical and manufacturing challenges of autologous products.
• Identifying novel biomarkers to predict therapeutic response and adverse events, allowing for personalized treatment strategies.
• Improving neurotoxicity monitoring tools, such as advanced imaging and neurophysiological assessments, especially for patients with pre-existing neurologic impairments.
• Studying the phenomenon of "immunologic reset" to understand how CAR T-cell therapy can lead to long-lasting drug-free remission even after B-cell reconstitution.

CAR T-cell therapy represents a paradigm shift in the treatment of neurologic immune-mediated diseases, offering a targeted, potentially curative option. Ongoing collaborative research will be essential to unlock its full potential for patients with conditions like multiple sclerosis and neuromyelitis optica spectrum disorder.

Bibliography

Brittain G, Roldan E, Alexander T, et al. The role of chimeric antigen receptor T-cell therapy in immune-mediated neurological diseases. Ann Neurol 2024;96:441-52. PMID 39015040

Brudno JN, Kochenderfer JN. Advances in the mechanism and management of CAR T cell toxicities. Nat Rev Clin Oncol 2024;21(7):501-21. PMID 38769449

Fischbach F, Richter J, Pfeffer LK, et al. CD19-targeted CAR T-cell therapy in two patients with MS. Med 2024;5:550-8. PMID 38554710

Haghikia A, Schett G, Mougiakakos D. B-cell-targeting chimeric antigen receptor T cells as an emerging therapy in neuroimmunological diseases. Lancet Neurol 2024;23(6):615-24. PMID 38760099

Liu Y, Dong M, Chu Y, et al. Dawn of CAR-T cell therapy in autoimmune diseases. Chin Med J (Engl) 2024;137(10):1140-50. PMID 38613216

Mitra A, Barua A, Huang L, et al. From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol 2023;14:1188049. PMID 37256141

Schubert ML, Schmitt M, Wang L, et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann Oncol 2021;32:34-8. PMID 33098993

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