CAR T-cell therapy shown to drive long-term remission in SLE patients
Ability to respond to vaccines not comprised in any of 8 patients treated
A CAR T-cell therapy targeting B-cells, a type of immune cells, was found to clear disease-causing autoantibodies from the bloodstream of eight people with systemic lupus erythematosus (SLE) — without compromising the patients’ ability to respond to vaccines — new trial data show.
The experimental therapy also drove the chronic disease into remission in each of the eight patients, who remained off all immunosuppressive medications for up to two years, despite the re-emergence of B-cells occurring a few months after the infusion.
The new data is being presented in a poster, titled “CAR T Cell Therapy Leads to Long-term Abrogation of Autoimmunity in SLE Patients While Vaccination Responses Are Maintained,” at the American College of Rheumatology’s ACR Convergence 2023. The annual meeting is being held Nov. 10-15 in San Diego, California.
“We were surprised … that despite the recurrence of B-cells, the disease remained absent,” Georg Schett, MD, a rheumatologist at the University Hospital Erlangen, in Germany, and the poster’s first author, said in an ACR press release.
“This outcome is the best one can expect as the presence of [B-cells] permits immune responses against infections and vaccinations, while the disease, including disease-associated autoantibodies, does not come back,” Schett said.
Researchers build on earlier use of CAR T-cell therapy
Autoimmune attacks in SLE are driven by autoantibodies that B-cells mistakenly produce against the body’s own tissues. Treatment often entails the use of immunosuppressants that keep the immune system in check, but not everyone responds to these medications.
In 2022, Schett’s team treated five people with SLE with a CAR T-cell therapy after other medications had failed to ease their lupus symptoms. At three months, all five patients achieved remission, which was maintained for up to a median of eight months after the infusion.
The therapy targets CD19, a protein found on the surface of B-cells. It involves collecting a patient’s own immune T-cells and altering them in the lab with a chimeric antigen receptor, or CAR, so that they are primed to attack the disease-causing B-cells once infused back into the body.
The aim of this follow-up study was to see whether this type of therapy could keep the disease in remission for a longer period of time. The researchers also wanted to find out whether depleting B-cells would make vaccines less effective for patients — given that vaccines generally rely on B-cells to trigger an immune response.
Between March 2021 and June 2023, eight people with treatment-resistant SLE received a single infusion of 1 million CAR T-cells per kilogram of body weight. After the infusion, disease activity was monitored for up to two years.
By June 2023, all eight patients were in remission. Their SLE Disease Activity Index-2000, or SLEDAI-2K, was zero, indicating no active disease. All of the patients also “were off glucocorticoid therapy and any other immunosuppressive medication,” the researchers wrote.
Autoantibody levels were measured at the study’s start, at three months, and at one to two years after receiving the CAR T-cell therapy. After the infusion, the autoantibodies disappeared, with the exception of a single autoantibody in one patient. All remained negative until the last follow-up.
This occurred in spite of the re-emergence of naïve B-cells, a type of B-cells that have not been exposed to an antigen — a substance that can trigger an immune response — a few months after the infusion.
Treated patients mounted immune responses against multiple vaccines
To investigate if CAR T-cell therapy might leave patients at a greater risk of contracting an infection, researchers also assessed their responses to vaccines against measles, mumps, rubella, varicella zoster virus, the Epstein-Barr virus, tetanus, and pneumococcus.
Patients mounted immune responses against these vaccines, suggesting that CAR T-cell therapy may lead “to a sustained disappearance of autoantibodies in SLE patients, while vaccination responses remained stable,” the researchers wrote.
This also suggests that the main source of disease-causing autoantibodies are CD19-positive B-cells, which are depleted with CAR T-cell therapy.
In contrast, according to Schett, “some antibodies are deeply anchored in long-lived blood cells, which are CD19-negative and therefore escape CD19-targeted CAR-T cell therapy.”
“Vaccination antibodies, such as tetanus, are a classic example,” Schett said.
The first patients treated will soon have 1,000 disease-free and drug-free days. We hope that responses sustain and think there may be a good chance for sustained responses, as we did not observe any regeneration of disease-associated autoantibodies.
Five of the patients were followed for more than a year after receiving treatment.
“The first patients treated will soon have 1,000 disease-free and drug-free days. We hope that responses sustain and think there may be a good chance for sustained responses, as we did not observe any regeneration of disease-associated autoantibodies,” Schett said.
The data thus far are promising, according to researchers.
“The selective and sustained abrogation [abolition] of [disease-specific] autoimmunity without affecting vaccination responses provides a favorable combination for the safety and efficacy of CD19 CAR [T-cell] therapy in SLE,” the team concluded.