CAR T-cell therapy rese-cel shows early efficacy in systemic sclerosis
Several other clinical trials testing treatment in autoimmune diseases
Two patients with systemic sclerosis (SSc) had reduced skin thickness after treatment with the investigational CAR T-cell therapy rese-cel (resecabtagene autoleucel) and discontinuation of immunomodulators and steroids.
These initial results came from the Phase 1/2 RESET-SSc clinical trial (NCT06328777), one of several trials that rese-cel developer Cabaletta Bio is running to test the therapy in autoimmune diseases. RESET-SSc is currently recruiting at several sites in the Midwest and eastern U.S. It aims to test the the safety, tolerability, and effectiveness of rese-cel in SSc, also named scleroderma.
The company discussed these results at the European Alliance of Associations for Rheumatology conference, held June 11–14 in Barcelona, Spain. The presentation was titled “RESET-SSc: Clinical Trial Evaluating Rese-cel (Resecabtagene Autoleucel), a Fully Human, Autologous 4-1BB Anti-CD19 CAR T Cell Therapy in Systemic Sclerosis.” Two additional presentations discussed RESET rese-cel trials for myositis and systemic lupus erythematosus (SLE), which also demonstrated early promise, according to Cabaletta.
“Patients are seeking a drug-free, symptom-free life, which is rarely, if ever, achieved with currently approved therapies,” David J. Chang, MD, chief medical officer of Cabaletta, said in a company press release. “We believe the clinical data on rese-cel indicate its potential to achieve this aspiration and ultimately change treatment paradigms for autoimmune diseases.”
SSc study to enroll adults with skin, organ involvement
In SSc, an overactive immune system causes inflammation and scar tissue buildup in the skin and connective tissue, which supports and holds organs together. Immune B-cells, which produce antibodies to help the body fight off diseases, are central to these inflammatory attacks when hyperactive.
Rese-cel, formerly known as CABA-201, aims to deplete B-cells. It involves collecting a patient’s own immune T-cells, modifying them to carry a chimeric antigen receptor (CAR) that binds to CD19, a protein on the surface of B-cells, and infusing them back into the patient.
“Persistent B cell activity in skin and lung tissue may contribute to treatment resistance using currently available therapies,” the researchers wrote in the presentation. “Initial patients treated with rese-cel have shown compelling clinical responses with safety data that supports development in autoimmune diseases.”
Ultimately, the RESET-SSc study seeks to enroll at least six adults with severe skin involvement and another six or more with organ involvement. Patients with severe lung or cardiac impairment will not be included in the trial.
Initial patients treated with rese-cel have shown compelling clinical responses with safety data that supports development in autoimmune diseases.
The company also released data from two participants, women ages 55 and 66 in the severe skin involvement group. These participants discontinued the immunomodulator therapy mycophenolate mofetil as well as steroids before receiving a single into-the-vein, or intravenous, infusion of rese-cel at 1x10E6 cells/kg.
No unexpected safety findings have been noted to date. One woman developed a condition called cytokine release syndrome, a systemic immune response triggered by some CAR T-cell therapies, beginning on day 10.
As previously reported, the other woman experienced immune effector cell-associated neurotoxicity syndrome, or ICANS, a common and usually reversible neurological complication of CAR T-cell therapy. She had no evidence of seizures and was able to speak, but answered all questions incorrectly. This complication resolved after treatment with dexamethasone, a corticosteroid.
Less severe skin thickening seen in women on rese-cel
Efficacy results showed B-cell depletion at three weeks post-infusion, followed by repopulation, or increased levels, by week eight in the woman with long enough follow-up. “B cells rapidly and transiently depleted in peripheral blood and tissue following rese-cel infusion,” the scientists wrote in the presentation.
In addition, the modified Rodnan Skin Score, a measure of skin thickness across 17 body areas, showed a trend toward less severe skin thickening in both women, reaching 24 weeks, or nearly six months, in the case with the longest follow-up.
That participant had interstitial lung disease at the beginning of the study, which stabilized after treatment. Measures of her lung function indicated improvements at weeks 12 and 24 post-infusion. She also met the revised CRISS, or Composite Response Index in Systemic Sclerosis, criteria — a measure of disease severity — after about three months. This result “[highlights] the potential of rese-cel to provide a drug-free, clinical response in patients with systemic sclerosis,” according to the company press release.
RESET-Myositis and RESET-SLE similarly found therapeutic effects with rese-cel. “These new clinical and translational findings reinforce our belief that a single, weight-based dose of rese-cel leads to deep B cell depletion and compelling clinical data in patients with myositis, lupus and systemic sclerosis, with nearly all patients off immunomodulators and steroids,” Chang said.
Cabaletta recently aligned with the U.S. Food and Drug Administration (FDA) on a clinical trial design for a pathway to approval of rese-cel for myositis. The company now hopes to achieve similar FDA agreements for scleroderma, SLE, and myasthenia gravis.
About the Author
