CAR-T cell therapy is showing promise in treating autoimmune diseases with minimal toxicities, according to recent data presented at the ACR Convergence 2024. Studies, including the CASTLE basket study and trials of Cabaletta Bio's CABA-201 and Bristol Myers Squibb's CC-97540, indicate significant clinical responses across various autoimmune conditions.
CASTLE Study: CAR-T for Lupus, Myositis, and Systemic Sclerosis
The CASTLE study, led by Georg Schett, MD, from Friedrich Alexander University Erlangen-Nürnberg, investigated the safety and efficacy of CD19-directed CAR-T cell therapy in patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc). The study included seven patients with SLE, three with IIM, and seven with SSc.
The primary safety endpoints focused on toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), organ toxicity, and hematotoxicity. Efficacy endpoints included DORIS remission for SLE, ACR/EULAR moderate/major response for IIM, and no worsening of symptoms, lung function, or CT changes in SSc.
According to Schett, the treatment resulted in "very robust CAR T-cell expansion." Of the 11 patients with six-month follow-up data, all six SLE patients entered DORIS remission, both IIM patients demonstrated a major response, and all three SSc patients showed no skin worsening. Notably, seven patients experienced no CRS, and none had it above grade 2. There were no instances of ICANS of any grade, and no patients had grade 4 leukocytopenia or neutropenia from one month onward.
Cabaletta Bio's CABA-201: Clinical Responses in Autoimmune Diseases
Cabaletta Bio presented data on CABA-201, an investigational CD19-directed CAR-T therapy, from the RESET-SLE, RESET-Myositis, and RESET-SSc clinical trials. In RESET-Myositis, a patient with immune-mediated necrotizing myopathy (IMNM) with six months of follow-up showed a sustained and improved clinical response without flares and was off immunosuppressants. Another IMNM patient and a dermatomyositis patient also showed significant improvements and were off immunosuppressants at one month post-treatment.
In RESET-SLE, three patients with nonrenal SLE had no clinical symptoms on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2000 at their latest follow-up. A patient with lupus nephritis (LN) improved from 22 to 8 on SLEDAI from baseline to four months of follow-up, with proteinuria approaching normal levels. A patient in RESET-SSc showed improvement in modified Rodnan Skin Score.
Safety Profile and Next-Generation Manufacturing
Across the Cabaletta Bio trials, no cases of CRS were reported in five of eight evaluable patients. The other three had grade 1 to 2 CRS, resolving with standard treatment. One LN patient experienced ICANS, potentially linked to an occult infection. Cabaletta is now implementing a two-week waiting period for patients with fever before CABA-201 infusion.
Bristol Myers Squibb's CC-97540 utilizes a next-generation manufacturing process, reducing production time to five days and requiring fewer cells for infusion. This fast manufacturing is seen as a significant advantage, potentially reducing turnaround time and production space needs.
Expert Perspectives
Georg Schett noted the low relapse rate in their center, with only one relapse out of over 40 patients treated. He emphasized that while relapses can occur, most patients experience drug-free remission for an extended period. David J. Chang, MD, Cabaletta's chief medical officer, highlighted the potential of CABA-201 to provide immunosuppressant-free clinical responses. Steven Nichtberger, MD, Cabaletta's CEO, expressed optimism about accelerating CABA-201 development, with plans to meet with the FDA to discuss potential registrational trial designs.
