B-cells disappeared from the bloodstream two days after infusion, results showed
by Lindsey Shapiro | October 24, 2022
A CAR T-cell therapy targeting disease-driving immune cells safely led to sustained disease remission for five people with systemic lupus erythematosus (SLE) who’d previously failed to respond to other treatments, a recent study reported.
Treatment was also highly specific, preventing autoimmune activity, but didn’t impair general immune system function.
“These data provide new therapeutic possibilities to control SLE disease activity,” the researchers wrote. “Longer follow-ups in larger cohorts of patients will be necessary to confirm sustained absence of autoimmunity and resolution of inflammation in patients with SLE who have received CAR T cell therapy.”
The study, “Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus,” was published in Nature Medicine.
B-cells are immune cells that produce antibodies. This includes both helpful antibodies that work to fight off infections as well as harmful self-reactive antibodies (autoantibodies) that drive autoimmune diseases such as SLE, the most common form of lupus.
A therapeutic approach for treating SLE is to deplete these antibody-producing cells. Medications that target the CD20 protein on B-cells, such as rituximab, are sometimes used for SLE but have shown limited efficacy, especially for people with more severe disease. That’s been attributed to the fact that many B-cells and their descendants called plasma cells escape elimination with this approach.
A chimeric antigen receptor (CAR) T-cell therapy targeting the CD19 protein on B-cells is one approach that could help thoroughly deplete these disease-driving cells. CD19 is widely and specifically found on B-cells and their descendants.
With CAR T-cell therapy, a patient’s immune T-cells are isolated from the bloodstream and engineered in the lab to express a lab-made receptor, or CAR, that’s specifically designed to recognize a disease-associated protein — in this case, CD19.
After a course of chemotherapy to reset a patient’s immune system, modified T-cells are re-infused back into the body, where they will recognize and attack the CD19-positive cells.
A number of CD19 CAR T-cell therapies are approved for certain forms of cancer, but haven’t been approved for SLE. Still, preclinical studies demonstrated this approach can reverse disease symptoms and prolong survival in SLE mouse models.
Assessing CAR T-cell safety, effectiveness
Researchers in Germany evaluated the safety and effectiveness of CD19 CAR T-cells in five SLE patients (four women and one man, ages 18–24) through a compassionate use program. All had active SLE with multi-organ involvement and had failed to respond to multiple prior immunotherapies.
After chemotherapy, they received CAR T-cells as a one-time infusion and then monitored in the hospital for 10 days before being released for outpatient follow-up.
Results showed B-cells fully disappeared from the patients’ bloodstream two days after the infusion. Other immune cell types, although temporarily decreased after treatment, rapidly recovered.
Disease activity was continuously monitored with the SLE Disease Activity Index-2000 (SLEDAI-2K), with higher scores reflecting greater disease activity.
At the study’s start, the patients had SLEDAI-2K scores ranging between 8–16. Disease activity continuously eased for all five after treatment, reaching a score of zero in four of them after three months.
Other clinical manifestations, including kidney inflammation, arthritis, fatigue, heart valve scarring, and lung involvement were also eliminated in patients who had those symptoms at the study’s start.
Signs of autoimmunity, including levels of SLE-associated antibodies and activation of the complement system, a driver of inflammation, eased after treatment, dropping below the clinical cutoff.
Ultimately, all five met the criteria for remission three months after treatment and all other immunosuppressive medications could be discontinued.
B-cells ended up re-emerging an average of 110 days (about 3.5 months) after the infusion. No patient had a clinical SLE relapse and all remained in drug-free remission for up to 17 months (in the longest followed participant), however.
Overall, “CAR T cell treatment is associated with abrogation of autoimmunity in patients with SLE and remains present even after the patients reconstitute their B cells,” the researchers wrote, noting the B-cells that did return showed signs of being naive, with characteristics indicating they were no longer primed to drive autoimmunity, suggesting treatment led to a “rebooted immune system.”
CAR T-cell therapy was generally well-tolerated. Three patients had mild cytokine release syndrome (CRS) — a type of immune response commonly observed with CAR T-cell therapy, which was temporary and easily treatable.
None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANS), a neurological complication seen after CAR T-cell treatment in other patient groups.
No patients had infections after treatment and circulating antibodies generated in response to prior vaccinations appeared unaffected, “indicating that the effects of CAR T cell therapy are primarily directed against autoantibody-producing cells rather than all [antibody]-producing cells,” the researchers wrote.