CAR-T cell therapy could lead to sustained suppression of autoantibodies in treatment-resistant lupus

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New research at ACR Convergence 2023, the annual meeting of the American College of Rheumatology, shows that CAR-T cell therapy can lead to sustained suppression of autoantibodies in treatment-resistant lupus while maintaining a robust response to vaccines (abstract #0607).

Systemic lupus erythematosus (SLE, lupus) is a complex autoimmune disease characterized by the production of autoantibodies to nucleic acid DNA and nuclear protein autoantigens and associated with dysfunctional B cells. It mainly affects women and is more common and severe in people who are black, Hispanic, or Asian. Lupus can lead to a wide range of systemic problems of varying severity, including skin, kidney, lung, joint and heart disease and complications during pregnancy.

The disease often requires lifelong treatment with immunosuppressive or immunomodulatory drugs, and a significant number of patients do not respond to them. A theoretical option for these patients is chimeric antigen receptor (CAR)-T cell therapy, which has been successfully used to treat refractory blood cancers by destroying malignant cells.

“We were intrigued by the possibility that a profound B cell depletion induced by CAR-T cells could lead to permanent eradication of autoimmune disease.”

Georg Schett, MD, rheumatologist, University Hospital Erlangen, Germany

CAR-T cells are made by removing some of the patient’s white blood cells, which include immune system T cells, and genetically modifying them in a lab to create chimeric antigen receptors (CARs). The changes allow the treated T cells to recognize and destroy antigens on the surface of target pathogenic cells after they return to the patient.

Shet and his colleagues published the first study of CAR-T therapy for lupus in 2022. The CAR-T cells were engineered to target CD19, a protein on the surface of B cells that triggers lupus flares. At three months, all five study patients achieved drug-free remission, which was maintained for a median of eight months after infusion.

The current follow-up study aimed to determine whether remission could be sustained in CD19 CAR-T cell-treated patients and whether depletion of B cells would blunt the efficacy of the vaccine, which works through B cells to drive antibody responses.

The study included eight patients, one of whom was an Asian woman. None were black or Hispanic. Patient T cells were modified using the lentiviral vector MBCART19. Lentiviral vectors are commonly used to deliver genetic material to specific cells in a lab. Between March 2021 and June 2023, each patient received a single dose of one million CD19 CAR-T cells per kilogram of body weight.

The researchers monitored the patients’ disease activity for up to two years. Autoantibodies were measured at baseline, three months after CAR-T cell therapy and one to two years after infusion using enzyme-linked immunosorbent assay (ELISA). Anti-double strand DNA was measured a second time by radioimmunoassay.

Researchers also evaluated how patients responded to vaccines against measles, mumps, rubella, varicella zoster virus, Epstein-Barr, tetanus and pneumococcus.

By June 2023, all eight patients were in remission, had zero SLE disease activity (SLEDAI) scores, and were off all immunosuppressant medications, including glucocorticoids. Autoantibodies disappeared after CAR-T cell therapy except for a single antibody in one patient who remained negative until last follow-up 12 to 24 months after treatment. This was despite the re-emergence of naïve B cells several months after the infusion, which may play a role in the patients’ robust immune response.

“We were surprised that despite the recurrence of B cells, the disease was absent,” says Shett. “This result is best expected as the presence of B cells allows an immune response against infection and vaccination, when the disease does not return with disease-associated autoantibodies.”

Schett explains the apparent contradiction this way: “Some antibodies anchor deeply in chronic blood cells, which are CD19-negative and therefore escape CD19-targeted CAR-T cell therapy. Vaccine antibodies such as tetanus are a classic example. On the other hand, double-stranded in SLE DNA and other antibodies appear to be based on plasmablasts, which are CD19-positive and [therefore destroyed] by CD19 CAR-T cells.”

Although the study results are encouraging, CAR-T cell therapy has several serious limitations, including potentially life-threatening toxicities such as cytokine release syndrome (CRS, cytokine storm) and immune effector cell-associated neurotoxicity syndrome (ICANS). There are also costs. In the United States, a single CAR-T infusion runs from $375,000 to $425,000. These prices do not take into account associated costs, which can be significant. If the infusion is administered in a hospital, the hospital stay may cost the same as the infusion.

Sheth says CAR-T therapy for lupus is safer than cancer, with fewer complications associated with CRS. And he noted that although therapy costs are high, they are country-dependent and can be offset by years of not needing expensive lupus drugs. “The tipping point here depends on the drugs used and the cost of the CAR-T cell treatment; maybe three to five years of drugs can be successful.”

It’s also important to note that CAR-T is not approved for lupus in the United States

Still, Shett believes CAR-T treatment is a viable way forward.

“The first patients treated will soon have 1,000 disease-free and drug-free days. We expect that the responses will be sustained and think there may be a good chance for a sustained response, as we have not observed any resurgence of disease-associated autoantibodies,” he said.

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