CAR T-cell immunotherapy shows early benefit in lupus-related ITP
Small case series finds responses in 6 treatment-resistant patients
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Six people with treatment-resistant immune thrombocytopenia (ITP) and underlying systemic lupus erythematosus (SLE) all achieved clinical responses to CAR T-cell immunotherapy, according to a small case series.
An examination of complete responders showed signs of a more complete immune reset in the bone marrow. In contrast, partial responses were associated with the persistence of disease-driving immune cells in the bone marrow and impaired maturation of megakaryocytes, the bone marrow cells that produce platelets.
CAR T therapy tested in small lupus-related ITP study
“CAR T cell therapy is safe and effective for [treatment-resistant] lupus-related ITP,” the researchers wrote in the study, “Anti-CD19 CAR T cell therapy for refractory SLE-ITP,” published in Med.
SLE, the most common form of lupus, is an autoimmune disease that can damage multiple tissues and organs, including the joints, skin, kidneys, heart, lungs, and brain.
ITP is a common manifestation of SLE, in which immune activity can drive platelet destruction and impair platelet production, increasing the risk of easy bruising and bleeding.
CAR T-cell therapy is a type of immunotherapy approved for certain hard-to-treat blood cancers and under development for several autoimmune diseases.
In this study, a research team in China reported findings from an investigator-initiated clinical study (NCT05930314)Â evaluating anti-CD19 CAR T-cell therapy in people with lupus complicated by ITP who had not responded to multiple standard therapies.
Treatment targets antibody-producing immune cells
The therapy involves collecting a patient’s immune T-cells and modifying them with a receptor called a chimeric antigen receptor (CAR). These receptors are designed to target CD19, a protein found on the surface of B-cells. When infused back into the patient, the reprogrammed T-cells eliminate CD19-carrying B-cells, including those that produce disease-driving antibodies.
The patients had lived with SLE-ITP for a median of 14.5 years, ranging from four to 25 years, and had already tried a median of eight different treatments without success. At the start of the study, platelet counts were markedly low, with a median of 11 x 109/L (normal range: 150-400 x 109/L), and three of the six patients had counts at or below 10 x 109/L.
After a median follow-up of 12 months, three patients achieved complete remission, with platelet counts of at least 100 × 109/L, and three achieved partial remission, with platelet counts of at least 30 × 109/L and a twofold increase from baseline. Responses came relatively quickly. The median time to achieve partial or complete response was two months, and platelet improvements remained stable for up to one year in five of the six patients.
All six patients were able to stop their immunosuppressant medications and reduce their steroid doses to 5 mg or less per day.
Immune cells reset after CAR T-cell therapy
Several disease-related antibodies in the blood declined after treatment. Platelet-targeting antibodies fell to undetectable levels in all six patients. Antinuclear antibody, a hallmark marker of lupus, became undetectable in three patients. Anti-double-stranded DNA antibodies, another lupus marker, dropped to undetectable levels in one patient but remained positive and fluctuating in two partial responders.
After infusion, CAR T-cells expanded rapidly in all patients, peaking around day 14, and remained detectable in the bloodstream throughout the 6- to 12-month follow-up. B-cells were cleared from the bloodstream by day seven in all patients and remained absent for a median of 83 days, or almost three months.
When B-cells reappeared, they were predominantly immature, “naïve” types, while memory B-cells, which can help drive autoimmune disease, remained at very low levels for at least six months.
The researchers collected bone marrow samples from all six patients before treatment and again at six months, then performed detailed single-cell molecular analysis.
Among those who achieved complete remission, the bone marrow showed signs of a more complete immune system reset: immature, early-stage B cells increased, while more mature B-cells, including memory B-cells and antibody-secreting cells, declined. Two of the three partial responders showed the opposite pattern or continued accumulation of these mature, disease-associated B-cell types.
Platelet-producing cells may affect response
Regarding platelet production, bone marrow cells that generate platelets, called megakaryocyte progenitors, showed high or restored activity in pathways involved in platelet production in complete responders.
In one partial responder, these same cells showed consistently low activity, both before and after treatment. This pattern was also detectable in the patient’s platelets before treatment began, suggesting that impaired platelet production, rather than immune-driven platelet destruction alone, may have contributed to the patient’s incomplete response.
No dose-limiting toxicities were observed. Two patients experienced mild, grade 1 cytokine release syndrome, an immune reaction that can occur after CAR T-cell therapy, and no cases of immune effector cell-associated neurotoxicity syndrome, or ICANS, occurred.
“Incomplete immune reset in the bone marrow, including dysfunctional B cell reconstitution and persistent megakaryopoietic impairment, may underlie the suboptimal responses to the CD19 CAR T cell therapy in [partial response] patients,” the team noted.
“CD19 CAR T cell therapy appeared feasible, safe, and efficacious in patients with refractory SLE-ITP, providing a rationale for further clinical trials,” the researchers concluded.
