The Evolution of CAR T Therapy and Its Use in Systemic Lupus Erythematosus

By Emily Littlejohn, DO, MPH

International research is underway to examine the use of engineered T cell therapy for adults with severe, refractory systemic lupus erythematosus (SLE). This presents an opportunity to consider chimeric antigen receptor (CAR) T-cell treatment in a larger context, and what it might mean for the future management of autoimmune diseases.

Beginning in 2017, CAR T therapies have been approved for treatment of blood malignancies. Phase 2 and 3 trials are now taking place to examine CAR T for a number of solid cancers as well as for human immunodeficiency virus (HIV).

For those of us in rheumatology working to advance options for our patients with SLE, an ongoing international phase 1 trial¹ at the Cleveland Clinic is expected to supply much-needed data on safety, efficacy and follow-up. As we consider the potential of CAR T therapy for autoimmune diseases, it is important to review and understand what we have learned so far.

Living drugs

CAR T cells are sometimes referred to as “living drug” immunotherapy. Chimeric antigen receptors (also referred to as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are proteins that have been engineered to give T cells the new ability to target a specific antigen. They are chimeric because they combine both antigen-binding and T cell-activating functions.

Treatment begins with isolating a patient’s white cells through apheresis and then selecting the T cells (CD4+ and CD8+) to be transfected with the coding DNA necessary to produce a new receptor capable of recognizing a target antigen. (In the case of current SLE trials, that is anti-CD19.) CAR T cells are then expanded ex vivo.

Next, the patient is given intravenous chemotherapy for leukodepletion, with the intention to make space for T cell expansion and “prime” the cytokine environment. The CAR T cells are then reinfused into the patient. Once the CAR cells bind to target cells, the innate signaling can turn on machinery to destroy the cell that is recognized (B cells).

With every new medical treatment or therapy comes risk of side effects. In the case of CAR-T therapy, there are two that are most worrisome: Cytokine release syndrome (CRS) and Immune effector cell–associated neurotoxicity syndrome (ICANS).

Cytokine release syndrome

When CAR T-cells bind to their target antigen, they proliferate and produce cytotoxic molecules that mediate the destruction of tumor or target cells: interferon-γ, granulocyte macrophage colony-stimulating factor, IL-10 and IL-6. Cytokines and/or cytokine storms can cause increased vascular permeability and third-spacing of fluid, which can result in vasodilation, decreased cardiac output, and intravascular volume depletion. Common features of CRS include fever, hypotension and hypoxia. Severe CRS can evolve into fulminant hemophagocytic lymphohistiocytosis (HLH), which requires inpatient admission to the hospital.

Management of CRS typically includes use of tocilizumab with steroids. Other agents, including siltuximab (Sylvant), infliximab (Remicade), etanercept and anakinra also have been used in clinical trials. Tocilizumab has not been shown to adversely affect the efficacy of CAR T-cell therapy.

Because corticosteroids are known to suppress and/or kill T cells, it is prudent to avoid their use for non–CAR T-cell–related adverse effects.

Immune effector cell–associated neurotoxicity syndrome

More serious side effects can include neurological symptoms, with or without CRS. Symptoms range from confusion, agitation and delirium and, in severe cases, receptive or expressive aphasia, obtundation, convulsive or nonconvulsive seizures, and cerebral edema. This may be due to greater blood-brain permeability allowing the therapeutic treatment to reach the central nervous system.

Management depends on severity. Low-grade neurologic events can be managed primarily with supportive care. For patients with grade ≥ 1 neurologic events with concurrent CRS, tocilizumab is recommended. Neurologic events without concurrent CRS do not respond to anti–IL-6 therapy. Grade ≥ 2 neurologic events not associated with CRS can be treated with corticosteroids, dose dependent on the grade of the event.

The rationale for use of T cell therapy for autoimmune diseases

The hallmark association of systemic lupus erythematosus with a diverse range of autoantibodies (anti-dsDNA and anti-Sm antibodies), and the presence of immune complex deposition in various tissues, makes depletion of B cells of interest in treatment of SLE. B cells and their multiple subtypes, including plasmablasts, have pathogenic capabilities beyond antibody production. This has led to an interest in them as therapeutic targets.

Histopathology studies of patients with antisynthetase syndrome have shown the presence of B cells and plasmablasts adjacent to T cells in the affected muscles. This condition is also associated with changes in the profile of peripheral B cells. B-cell depleting therapy with rituximab has been efficacious in a subset of patients with antisynthetase syndrome, which supports the pathogenic role of autoreactive B cells.

Many previous B-cell-directed therapies have not reached primary endpoints or produced positive or consistent results. They have failed to achieve deep tissue depletion of B cells and shown an inability to target late-stage B cells such as plasmablasts, which are implicated in disease pathogenesis.

State of the research

Results of recent studies of CAR T cell therapy in SLE and antisynthetase syndrome have offered rationale for further research.

In 2022, Nature Medicine published results of a study² from a single site in Germany, in which four women and one man, aged 18 to 24, received compassionate use of anti-CD19 CAR T therapy for their severe, refractory SLE. All had multiorgan involvement and failed to respond to multiple therapies, including pulsed glucocorticoids, hydroxychloroquine, belimumab, azathioprine, mycophenolate mofetil, cyclophosphamide and rituximab.

Following treatment, nephritis ceased in all five patients. Arthritis, fatigue, fibrosis of cardiac valves and lung restriction/diffusion impairment disappeared. INF-a, which had been present in three patients at enrollment, was undetectable in all patients at follow-up. All DMARD/immunomodulatory drugs, including hydroxychloroquine and steroids, were discontinued. Two patients sustained mild CRS. Of note, CRS risk appeared to be much lower than what is seen in studies of CAR T cell therapies for malignancies.

The study was limited by its small sample size and follow-up data, which ranged from five to 17 months. More recent data indicates that one patient has remained in drug-free remission for 600 days. As of early 2024, all patients with SLE had met Definition Of Remission In SLE (DORIS) criteria. Median follow-up was 15 months.³

A study⁴ assessing the efficacy of the therapy on two patients with antisynthetase syndrome showed similar results. Both patients experienced normalization or significant reduction in CK levels (patient 1: CK+120 days: 70U/l; patient 2: CK+60 days: 311U/l) and were able to stop all immunosuppressive therapy. Follow-up CT scans of the lung and MRI of the thigh done in patient 1 showed resolution of alveolar inflammation and mitigation of inflammatory changes in the thigh muscles and the hamstrings. Highly positive anti-Jo1 antibodies (331U/l) disappeared after CAR-T. Both patients reported near-total elimination of their severe symptoms within about four months of dosing. At the latest follow up (120 days and 60 days) both patients were in drug-free remission.

Multicenter studies using CAR T therapy that are now under way in the U.S. and Europe stand to offer new insights into approaches for addressing unmet needs in some of rheumatology’s most difficult diseases. It is our hope that CAR T therapy will one day be a life changing therapeutic option for all our patients.

Notes

1. https://clinicaltrials.gov/study/NCT05869955.

2. Mackensen A, eta al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132.

3. Müller F, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med. 2024 Feb 22;390(8):687-700. doi: 10.1056/NEJMoa2308917. PMID: 38381673.

4. Taubmann J, Müller F, Boeltz S, et alPOS1238 First evidence for efficacy of CAR-t cell treatment in refractory antisynthetase syndrome, Annals of the Rheumatic Diseases 2023;82:957-958.