The first clinical data for an mRNA-lipid nanoparticle (mRNA-LNP)- based in vivo CAR T-cell candidate, HN2301*, developed by MagicRNA, were published in The New England Journal of Medicine. [1] The study results represent the first-ever demonstration of in vivo CAR T-cell generation and activity in patients diagnosed with refractory systemic lupus erythematosus (rSLE), a chronic, multisystem autoimmune disease affecting an estimated 3.4 million people globally, with a prevalence of approximately 44 per 100,000 individuals.**
Clinical data supports the safety and efficacy of in vivo CAR-T Therapy in refractory systemic lupus erythematosus (SLE) patients.
The data demonstrated that a low dose of HN2301 reprogrammed up to 60% of CD8+ CAR+ T cells in patients’ peripheral blood, resulting in complete depletion of circulating B cells and up to a 20-point reduction in SLEDAI scores within 3 months.
The study results also showed a favourable safety profile, with no neurotoxic effects or other severe adverse events, and no clinically significant elevation of liver enzymes observed during or after treatment in any of the 5 patients.
“This study is an important milestone for the entire field of cell therapy,” said Prof. Georg Schett, a pioneer in the use of CD19 CAR T-cell therapy in SLE, who achieved a revolutionary breakthrough.
“For the first time, we see functional CAR T-cells generated directly in patients’ body, achieving rapid B-cell clearance and clinical improvement of autoimmune disease. These findings, together with the favorable safety profile, pave the way for a new era of immunotherapy,” Schett added.
The clinical trial enrolled five patients with long-standing, treatment-refractory SLE, four of whom also had lupus nephritis. Built on MagicRNA’s EnC-LNP delivery platform technology, HN2301 was administered intravenously without prior lymphodepletion to deliver CAR-encoding mRNA to CD8+ T cells, reprogramming them into CD19-targeted CAR T cells in vivo.
“This study marks the first clinical proof-of-concept of the cell-targeted-LNP-based in vivo CAR T-cell in autoimmune disease, validating its therapeutic potential in patients,” explained Gavin Zha, MD, PhD, CEO of MagicRNA.
“By achieving deep B-cell depletion, in vivo CAR T technology offers a new level of disease control that potentially goes beyond what has been achieved with conventional approaches such as monoclonal antibodies and T-cell engagers. At the same time, it overcomes the major limitations of ex vivo CAR T therapies, including complex manufacturing, long preparation times, high costs, and the requirement for lymphodepletion. Our platform has the potential to make transformative cell therapies broadly accessible and scalable for patients,” Zha explained.
At a minimal dose (2 mg per infusion), single or repeated administration of HN2301 induced CAR T-cells generation and B-cell reduction. At a bit higher dose (4 mg per infusion) up to 60% of CD8+ CAR+T-cells were reprogrammed within six hours, leading to complete depletion of circulating B cells, which persisted for 7-10 days. Consistent with B-cell depletion, anti-nucleosome and anti-dsDNA antibodies significantly decreased, and low complement levels in some patients normalized at the last visit. In addition, Disease Activity Index (SLEDAI-2000) scores decreased by as much as 20 points in all 5 patients 3 months after HN2301 infusion. The treatment was generally well tolerated; no patients experienced grade ≥3 CRS, and no neurotoxic effects or other severe adverse events were observed during or after treatment.
Based on these encouraging clinical results, MagicRNA will continue the dose-escalation studies to evaluate further HN2301’s ability to achieve immune reset and long-term drug-free remission, accelerate clinical development, and ultimately bring this therapy to patients worldwide.
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Note: * HN2301 encapsulates CD19 CAR-encoding mRNA in a proprietary T-cell-targeted lipid nanoparticle (EnC-LNP), enabling direct reprogramming of patient T cells into functional CAR T cells in vivo. In preclinical studies, including nonhuman primate and mouse models, HN2301 achieved rapid and robust CAR T reprogramming and complete B-cell depletion in blood and tissues. Early first-in-human data demonstrated feasibility, clinical efficacy, and a favourable safety profile.
** Refractory systemic lupus erythematosus (rSLE) disproportionately affects women of childbearing age and is characterized by immune-mediated inflammation and tissue damage across multiple organs, with lupus nephritis being one of the most severe and life-threatening manifestations. Traditional standard treatments for SLE, including corticosteroids, immunosuppressants, and biologics, can help control symptoms, but many patients continue to experience recurrent relapses, driving progressive multiple-tissue damage and life-threatening complications. B cells play a pivotal role in the pathogenesis of SLE by producing autoantibodies, and the “B cell reset”-induced drug-free remission of SLE has been extensively validated by clinical reports
Clinical trials
Efficacy and Safety of HN2301 in Refractory Systemic Lupus Erythematosus (SLE) – ClinicalTrials.gov ID NCT06801119
Reference
[1] Wang Q, Xiao ZX, Zheng X, Wang G, Yang L, Shi L, Xiang N, Wang X, Zha GF, Schett G, Chen Z. In Vivo CD19 CAR T-Cell Therapy for Refractory Systemic Lupus Erythematosus. N Engl J Med. 2025 Oct 16;393(15):1542-1544. doi: 10.1056/NEJMc2509522. Epub 2025 Sep 17. PMID: 40961420.
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