Allogeneic Anti-CD19 CAR-T Therapy TyU19 Achieves Sustained Remission in Refractory Systemic Lupus Erythematosus: First-in-Class Clinical Evidence from China

Author: Wang Cong

Editor | Wang Duoyu

Typesetting丨Chengwen Shui

This single-center pilot study initiated by the researchers（NCT05988216）In China, the research team evaluated allogeneic CD19-targeted CAR-T cells.（TyU19）Safety and Efficacy in Refractory Systemic Lupus Erythematosus.

TyU19Was developed by BRL MedicineNew Generation AllogeneicUniversal CAR-T Cell Therapy，Using CRISPR-Cas9 gene editing technology to genetically engineer CD19-targeted CAR-T cells derived from healthy donors to address immune rejection issues.

From September 2023 to September 2024, the study enrolled four patients aged 22-24 with refractory systemic lupus erythematosus.（SLE）Young Female Patient(Patient IDS01、S02、S03、S04）, with baseline SELENA-SLEDAI scores ranging from 14 to 26. All patients had a history of multi-organ involvement.Among themS01, S02, S03 patients also experienced lupus encephalopathy.(but none of them showed active central nervous system lupus at enrollment), including a history of various immunosuppressants and biologics.

The treatment regimen is shown in the figure below. Patients S01, S02, and S03 received lymphodepleting chemotherapy, including intravenous injection of fludarabine on days 5, 4, and 3, as well as intravenous injection of cyclophosphamide on days 5 and 4.All patients received 1× on Day 0.10⁶A CAR-T cellInfusion at a dose of cells/kg. Patient S04 received prior to enrollment.Telitacip（telitacicept）Treatment, therefore, requires a 6-week washout period. However, during this washout period, the disease progressed, manifested by worsening joint pain, chest tightness, and low-grade fever, necessitating the use of cyclophosphamide to control the condition. After an additional two-week washout period, without further lymphocyte depletion, CAR-T cells were directly infused.

After receiving treatment, all four patients showed continuous improvement in clinical signs and symptoms. At the 3-month follow-up, all four patients had sustained relief, achieved a SELENA-SLEDAI score of zero at 3-6 months, and had a PGA score of less than 1. Arthritis(Patients S02, S03, and S04), Hair Loss(Patients S01, S02, S03, and S04)And finger vasculitis/ulcer(Patients S01 and S04)The symptoms have all disappeared. The complement factors C3 and C4 of all patients returned to normal within one month. The anti-dsDNA antibody levels of all patients decreased, and proteinuria also completely disappeared.Anti-Smith Levels of antibodies against antigens, U1-RNP, and Ro52 significantly decreased.

Importantly, patient S01 discontinued all immunomodulators and immunosuppressants, including glucocorticoids, at 3 months, achieving drug-free remission. The other three patients are currently still undergoing maintenance therapy with low-dose corticosteroids. The use of low-dose corticosteroid therapy with gradual tapering may help maintain and consolidate the clinical efficacy previously achieved.

In the first few weeks, the most common grade 3 or 4 adverse events were neutropenia, lymphopenia, hepatic dysfunction, fever, and fatigue. Neutropenia and lymphopenia were attributed to the lymphodepleting conditioning regimen. All patients experienced only grade 1 cytokine release syndrome.（CRS）, manifested as fever, lasting for 2-3 days. During the treatment period, no patients developed immune effector cell-associated neurotoxicity syndrome.（ICANS）or Graft-versus-Host Disease（GvHD）Cytokines and C-Reactive Protein（CRP）Levels were closely monitored and no significant increase was observed. Patients S02, S03, and S04 experienced a decline in IgA, IgG, and IgM levels after receiving CAR-T cell infusion. Comparative analysis of hepatitis B antibody titers conducted before and three months after CAR-T cell infusion showed no significant weakening of vaccine response. No infections occurred in all patients during hospitalization or follow-up.. PatientOral administration of acyclovir and sulfamethoxazole until B cell recovery.

To reduce the risk of host immune rejection against allogeneic CAR-T cells, a more intensive lymphodepletion regimen than that used in autologous CAR-T therapy is typically employed before infusion. This often involves the use of anti-CD52 antibodies, resulting in enhanced immunosuppression and an increased incidence of adverse events, particularly severe infections.

TyU19 Achieves Systematic Knockout of TRAC, HLA-A, HLA-B, CIITA, and PD-1 Genes via CRISPR-Cas9 Gene Editing Technology, Demonstrating Significant Innovative Breakthroughs. Compared with Conventional CAR-T Cell Therapy, TyU19 Only Requires a Very Low-Intensity Lymphodepletion Regimen Before Treatment—The research team even attempted a completely new treatment model of "non-clearance reinfusion" in this clinical trial.Excitingly, even without lymphodepletion preconditioning, TyU19 still demonstrated excellent therapeutic effects. This breakthrough progress has opened up a new path for the treatment of autoimmune diseases, showcasing the great clinical transformation potential of this method.

July 16, 2024BRL MedicineUnitedResearchers from East China Normal University and Shanghai Changzheng Hospital, in the top international academic journalCellPublished a paper in【2】。

The study utilizedTyU19 TherapySuccessTreated 1 caseRefractory Immune-Mediated Necrotizing MyopathyPatients and 2 casesDiffuse Cutaneous Systemic SclerosisPatients. During the 6-month follow-up period after treatment, all three patients experienced deep remission of their symptoms.The Disease Clinical Response Index score significantly improved, with inflammation and organ fibrosis also being reversed, andNo cytokine release syndrome or other serious adverse events, confirming the safety of gene-edited modifications.TyU19 Therapy Demonstrates Excellent Safety and Efficacy in the Treatment of Autoimmune Diseases.

This isThe world's first report of successful treatment of autoimmune diseases using allogeneic universal CAR-T cells.It is also a top academic journal.CellFirst Publication of CAR-T Cell Therapy for Autoimmune Diseases Research。

Published this time inCell Research's paper thenThe First Report on Allogeneic Universal CAR-T Cells in RefractorySystemic Lupus Erythematosus（SLE）Clinical application in patients has demonstrated significant clinical relief effects and good safety, thereby expanding the potential application of allogeneic universal CAR-T cell therapy in the treatment of autoimmune diseases.

A notable characteristic of systemic lupus erythematosus is the presence of autoantibodies produced by abnormal plasma cells and B cells, among which long-lived plasma cells...（LLPC）Mainly enriched in CD19^- CD38^hi CD138^hiPlasma Cell Subsets, which is an important source of autoantibody production. In autoantibody-mediated autoimmune diseases, long-lived plasma cells do not express CD19. Before treatment, the research team observed a significant number of CD19^- BCMA⁺ Cells, but all patients showed significant clinical improvement after receiving the treatment, and in all patients, the peripheral blood...BCMA⁺andCD19^- BCMA⁺ The reduction in plasma cells suggests that TyU19 mayTwo-pronged approach(Clear abnormal B cells + inhibit plasma cell regeneration)Achieve a long-term environment.

Overall, the study shows,Allogeneic CD19-Targeted CAR-T Cells（TyU19）In patients with refractory systemic lupus erythematosus, safety and efficacy have been demonstrated, especially in one patient who achieved sustained drug-free remission. This highlights the potential advantages of allogeneic CAR-T cell therapy as a promising treatment for patients with refractory systemic lupus erythematosus. Further research is necessary to explore its long-term efficacy and optimize its application in this challenging disease.

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