Long-Term Case Series Supports CAR-T Therapy in Autoimmune Disease


A 2-year evaluation of a small cohort of patients with systemic lupus erythematosus, idiopathic inflammatory myositis, and systemic sclerosis showed safety and efficacy which were supportive of additional clinical trials.

Georg Schett, MD, the vice president of research and a professor of internal medicine at Friedrich-Alexander University Erlangen-Nürnberg

Georg Schett, MD

(Credit: Friedrich-Alexander University Erlangen-Nürnberg)

Long-term, 2-year data from a case series involving 15 total patients treated with single infusion of CD19 chimeric antigen receptor (CAR) T cells published in the New England Journal of Medicine suggest that this avenue of therapy is feasible, safe, and efficacious in autoimmune diseases.1 This offers some supportive rationale for further controlled clinical trials in an area where interest in CAR T therapy is blossoming.2

Led by a group of investigators based in Germany headed by Georg Schett, MD, the vice president of research and a professor of internal medicine at Friedrich-Alexander University Erlangen-Nürnberg, the series included 8 patients with severe systemic lupus erythematosus (SLE), 3 patients with idiopathic inflammatory myositis, and 4 patients with systemic sclerosis. These individuals were preconditioned with fludarabine and cyclophosphamide, and then treated with a single infusion of CAR T cells. The median follow-up with these patients was 15 months (range, 4-29; IQR, 7 to 19), and the mean duration of B-cell aplasia was 112 days (±47).1

Efficacy was assessed via Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology–European League against Rheumatism (ACR–EULAR) major clinical response, and patient scores on the European Scleroderma Trials and Research Group (EUSTAR) activity index. Safety variables, including cytokine release syndrome and infections, were also recorded for the length of the study. Notably, all 15 patients successfully discontinued glucocorticoids and all other immunosuppressive medications as of the final follow-up.

“Despite differences in disease entities and previous treatments, the dynamics of CAR T-cell expansion and of B-cell ablation were highly consistent among patients. CD19 CAR T-cell therapy was effective independent of previous B-cell targeting by monoclonal antibodies,” Schett and colleagues wrote, adding that because of the lack of approved monoclonal antibodies targeting B cells for these 3 autoimmune diseases, they did not require participating patients to have prior exposure to these therapies. “It is notable that all the patients could successfully stop their immunosuppressive medication without having relapses or worsening of their disease,” they noted.

READ MORE: Understanding Disease Pathobiology Will be Key to Developing Cell Therapies for Autoimmune Disease

All told, after 6 months, 100% of the patients with SLE met the Lupus Low Disease Activity State (LLDA) criteria and reported DORIS remission, with SLE Disease Activity Index 2000 (SLEDAI-2K) scores of 0—the SLEDAI-2K scale ranges from 0 to 105, with higher scores indicating greater disease activity. This remained the case for patients with SLE at 29 months. “Furthermore, anti-dsDNA antibodies disappeared and remained negative, complement factor C3 levels normalized, and proteinuria disappeared during the entire observation period,” Schett and colleagues wrote.

One patient with SLE experienced proteinuria rebound 4 months post–CAR-T treatment, but this patient did not have a relapse, nor any signs of lupus nephritis on histopathology exams. Schett et al noted that, at the final 24-moth follow-up, this individual reported “only very mild proteinuria.”

For those 3 patients with idiopathic inflammatory myositis, a 3-month ACR–EULAR major clinical response was reported alongside a normalization of creatine kinase levels. These responses were maintained over the course of the study. Muscular function was also measured by Manual Muscle Test–8 (MMT-8) score, which was normalized in every patient (scores remained around 150 after 3 months, indicating stronger muscles. Additionally, extramuscular disease activity—measured by the visual-analogue scale of extramuscular symptoms—dropped sharply after 3 months and ceased around 9 months, which was maintained to the 12-month point.

Likewise, global disease activity defined by EUSTAR activity index score, as well as skin activity (measured by modified Rodnan skin score), decreased in all 4 patients with systemic sclerosis. “In the 3 patients with at least 6 months of follow-up, the median change in the EUSTAR activity index was −4.2 points (IQR, −4.7 to −2.3) and in the modified Rodnan skin score was −9 points (IQR, −17 to −7),” Schett et al wrote.

As for safety, adverse effects (AEs) of CD19 CAR T-cell treatment were deemed marginal, with no instances of high-grade cytokine release syndrome (CRS)—there were Grade 1 CRS instances in 10 patients, and 1 patient reported Grade 2 CRS—nor any concerning cases of immune effector cell–associated neurotoxicity syndrome (ICANS)—though 1 patient did report Grade 1 ICANS—and no prolonged bone marrow toxic effects. Instances of CRS occurred a median of 1 day (IQR, 1-7) after treatment, and lasted for a median of 5 days (IQR, 2-7). Another patient did report pneumonia 7 weeks after treatment that resulted in hospitalization, but this was resolved with antibiotic treatment.

Schett and colleagues noted that “nonetheless, careful monitoring of these patients is warranted because immunoglobulin levels decreased to some extent and infections occurred during the follow-up,” and that, additionally, “although a decrease of immunoglobulin levels after CD19 CAR T-cell therapy is expected owing to the elimination of antibody-producing plasmablasts, a substantial proportion of serum immunoglobulins, such as vaccination-related antibodies, were not eliminated, which implies that CD19-negative plasma cells may not be substantially affected by the therapy.”

Further Reading

In an editorial accompanying the case series, John D. Isaacs, MD, PhD, discusses the data at length, offering insight into the future trajectory of CAR T-cell therapy for autoimmunity—and the drivers of efficacy, safety, cost, and acceptability.

Click here to read his editorial in the New England Journal of Medicine:

Ultimately, the investigators concluded that these data provide new efficacy for this therapeutic approach in autoimmune disease, but randomized, controlled clinical studies will still be necessary. “Even though it is premature to judge whether these patients are indeed cured from their autoimmune disease, CD19 CAR T cells at least appear to be able to achieve sustained disease- and drug-free remission,” they concluded.

Recently, CGTLive® has spent time discussing the introduction of CAR T therapies into the autoimmune disease care paradigm, including a recent conversation with David Porter, MD, the director of Cell Therapy and Transplant and Jodi Fisher Horowitz Professor in Leukemia Care Excellence at the University of Pennsylvania Medicine. Porter discussed much about these treatments, as several players have entered the pipeline, including Kyverna Therapeutics’ KYV-101 and Nkarta’s NKX019 in lupus nephritis, ImmPACT Bio’s IMPT-514 and Gracell Bio’s GC012F in SLE, and Cabaletta Bio’s CABA-201 and Artiva Bio’s AB-101 being investigated in both SLE and lupus nephritis.

Porter also offered detail about some of the considerations that have to be kept in mind with the shift of these therapies from oncology to autoimmune diseases. Chief among his concerns was the importance of specialized training and experience with administering, monitoring, and caring for patients receiving CAR T-cell therapies given the potential for serious adverse events. Watch the video below to hear more of his perspective.

1. Fabian M, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up. N Engl J Med. 2024;390(8):687-700. doi:10.1056/NEJMoa2308917
2. Isaacs JD. CAR T Cells — A New Horizon for Autoimmunity? N Engl J Med. 2024;390(8):758-759. doi:10.1056/NEJMe240020
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