CAR T therapy shows ‘no major hematotoxicites’ in autoimmune disease phase 1/2 study
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WASHINGTON — A phase 1/2 study of CD19 chimeric antigen receptor T-cell therapy in lupus and other autoimmune diseases demonstrated significant response with minimal toxicities, according to data presented at ACR Convergence 2024.
“CASTLE is, in a nutshell, an autologous CAR T-cell approach,” Georg Schett, MD, of Friedrich Alexander University Erlangen-Nürnberg, in Germany, told attendees of the study. “It targets CD19, which is expressed by a variety of B cells. It’s a bread-and-butter approach, I would say, to treat autoimmune disease with CAR T cells.”
To investigate the safety and efficacy of CAR T-cell therapy in autoimmune diseases, Schett and colleagues initiated the ongoing CASTLE study, which so far includes seven patients with systemic lupus erythematosus, three patients with idiopathic inflammatory myositis (IIM), and seven patients with systemic sclerosis.
The primary safety endpoints are toxicities — including cytokine release syndrome, ICANS, organ toxicity and hematotoxicity, at grade 2 or higher for all — while efficacy endpoints are DORIS remission for SLE, ACR/EULAR moderate/major response for IIM, and no worsened symptoms, lung function or CT changes in SSc.
According to Schett, the treatment yielded “very robust CAR T-cell expansion, with a peak at 10 days in all of the patients.” Of the 11 patients with 6-month follow-up data, all six patients with SLE entered DORIS remission, both patients with IIM demonstrated major response, and all three SSc patients exhibited no skin worsening.
Regarding safety, seven patients demonstrated no cytokine release syndrome, and none had it above grade 2, while no patients had ICANS of any grade. Additionally, no patients had grade 4 leukocytopenia or grade 4 neutropenia from 1 month onward.
“To conclude, the predefined toxicity and efficacy endpoints were met, allowing us to proceed to the second part of CASTLE, and we suggest we will finish the second part of CASTLE in January 2025,” Schett said. “CRS was low grade, ICANS did not occur, no major hematotoxicites were observed, and we saw high-level responses in all three diseases.”
Perspective
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N. Lawrence Edwards, MD, MACP, MACR
This study is a major step toward advancing immunotherapy as treatment for autoimmune diseases. CAR T-cell therapy has shown success in pediatric and adult hematologic malignancies and is making its way into solid tumors as well, but, to this point, has not been successfully applied to autoimmunity, the opposite side of the coin from cancer therapy.
As a first step in these studies, identifying any unique or novel toxicities among autoimmune patients vs. cancer patients is a must. In this study, no higher grade cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANs), or direct myelotoxicity was observed. This is important since these patients with overactive immune systems pose a theoretical risk for more intense or prolonged CRS activation.
In this initial safety study, only one patient experienced grade 2 or higher CRS or ICANs, which is well within the expected event rate. Although not designed to show overall efficacy, it is important to note that observed responses to therapy were seen in eight of 11 patients, including six patients with systemic lupus erythematosus achieving remission and one with idiopathic inflammatory myositis achieving moderate/major response.
This study highlights the potential for CAR T-cell therapy as a safe and potentially effective treatment for refractory and difficult-to-treat autoimmune diseases. These results need confirmation in larger populations and long term follow up.
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Schett G. Abstract #1750. Presented at: ACR Convergence 2024; Nov. 14-19, 2024; Washington, D.C.
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