A basket trial from Georg Schett’s group hits across lupus, scleroderma and myositis.
A single infusion of CD19 CAR-T cells has driven drug-free remission in most patients with severe, treatment-refractory SLE, systemic sclerosis and inflammatory myopathies without high-grade cytokine release syndrome or any Immune effector cell-associated neurotoxicity syndrome, results from a trial have shown.
Findings from the phase 1/2a CASTLE trial position B-cell–targeted CAR-T therapy as a credible immune-reset strategy for some of the most difficult cases seen in rheumatology practice, the researchers say.
Their results have been published in Nature Medicine.
CASTLE (CAR-T cells in systemic B cell mediated autoimmune disease) prospectively tested zorpocabtagene autoleucel (Zorpo-cel; MB-CART19.1), an autologous CD19 CAR-T product, in 24 patients with highly active disease who had failed or not tolerated a median of four prior immunosuppressive regimens.
Of these, 10 patients had SLE, nine had SSc and five had IIM. All discontinued background immunosuppression before leukapheresis and received standard lymphodepletion with fludarabine and cyclophosphamide prior to a single CAR-T infusion.
Safety outcomes were favourable relative to oncology experience. No cytokine release syndrome (CRS) above grade 2 occurred and no immune effector cell–associated neurotoxicity syndrome (ICANS) was observed.
Most patients developed low-grade CRS, managed with tocilizumab in many cases.
Cytopenias were largely attributable to lymphodepletion, although delayed grade 3 neutropenia occurred in a small number of patients and resolved with granulocyte colony-stimulating factor.
Hypogammaglobulinemia emerged in some patients, with intravenous immunoglobulin required in selected cases.
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Four SLE flares occurred during the pre-infusion drug-free interval, and one patient experienced grade 3 kidney injury in the context of flare and cytomegalovirus reactivation, highlighting the need to optimise bridging strategies, the researchers noted.
At 24 weeks, 22 of the 24 patients met prespecified efficacy endpoints. Nine out of 10 patients with SLE achieved DORIS remission, accompanied by marked reductions in disease activity and serologic improvement.
All nine patients with SSc met the endpoint of no interstitial lung disease progression, with reported improvements in lung function and skin scores.
Four out of the five patients with inflammatory myopathy achieved ACR major or moderate response.
All participants remained free of glucocorticoids and other immunosuppressive therapies during the 24-week observation period.
Within a median follow-up of 13 (eight to 19) months, no relapses have occurred among the 24 CASTLE patients, the researchers reported.
Biologic analyses showed rapid B-cell depletion followed by reconstitution dominated by naive B cells, consistent with an immune reset. Many autoantibodies declined substantially, while most vaccine-related antibody titers were preserved.
Although limited by small size and lack of a control arm, the researchers said CASTLE provided the strongest prospective evidence to date that CD19 CAR-T therapy may achieve sustained, drug-free disease control in selected patients with severe B cell–mediated autoimmune disease.
“In summary, the CASTLE study showed safety and preliminary efficacy of Zorpo-cel in patients with SLE, SSc and IIM,” the researchers concluded.
“The once-in-a-time treatment approach leading to sustained drug-free remission is particularly attractive and unprecedented in autoimmune disease. T cell engagers targeting B cells and plasma cells have shown efficacy in treatment-refractory autoimmune diseases.
“So far, it is unclear whether such agents can indeed reset the immune system, similar to CAR-T cells, and allow the achievement of sustained drug-free remission. Innovative trial designs are needed to answer this question.
“CASTLE adds substantial new insights into CD19 CAR-T cell therapy of autoimmune disease and will help to design the pivotal study on Zorpo-cel in autoimmune diseases.”
