1. What are autoimmune diseases?

Autoimmune diseases are a group of heterogeneous diseases that are characterized by the destruction of immune tolerance. Allergic reactions to antigens can lead to the formation of autoreactive T cells and B cells, and then to the production of autoantibodies that attack their own organs. Autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, papular urticaria, and multiple sclerosis. In all autoimmune diseases, autoreactive B cell clones and autoantibodies against the patient's autoantigens often precede the onset of clinical symptoms. However, not all chronic inflammatory diseases are autoimmune diseases. For example, B cell mediation has not been found in the pathophysiology of diseases such as psoriasis, Crohn's disease or ankylosing spondylitis, but is clinically presents as chronic inflammation.

Autoimmune circulation that triggers chronic inflammation and tissue damage

2. Why can CAR-T treat autoimmune diseases?

 Autoimmune diseases can be treated by CAR T cells that recognize B cell-specific surface molecules: NIH National Cancer Institute James N. Kochenderfer Communication published the paper "Chimeric antigen receptor T cell therapy for autoimmune disease" in Nature reviews immunology, making a comprehensive analysis of the current situation and future direction of CART cell treatment for autoimmune diseases.

 A central principle of targeting B cells in autoimmune diseases stems from the critical role of B cells in driving pathogenesis through the production of autoantibodies, antigen presentation, and production of inflammatory cytokines. In clinical trials of systemic lupus erythematosus (SLE), anti-synthetase antibody syndrome, systemic sclerosis, and myasthenia gravis, anti-CD19 CAR T cells have shown substantial clearance of B cells including tissue-intrinsic B cells and plasmablasts. Importantly, these early studies reported rapid disease control and a good safety profile, with minimal cytokine release syndrome (CRS) or neurotoxicity observed compared to the oncology setting.

In autoimmune diseases, CARs targeting B cells are used to target the B cell-specific surface molecule CD19. After amplification and a usual combination of Flu and Cy, CAR T cells were reinfused into the patient to further expand and remove all CD19 expressing cells. To expand and clear all B cells expressing CD19. CD19-negative cells (including long-lived plasma cells in the bone marrow) were not subject to CART cell-mediated cytotoxicity.

Principle of autologous CAR-T cell therapy

3. Clinical study of universal CAR-T treatment for autoimmune diseases

 A initial efficacy response was first observed in autologous CD19 CAR-T cells in 2021, Five subsequent SAEs in 2022 were also shown to have an encouraging efficacy response to autologous CD19 CAR-T therapy, last year, Dr. Fabian Muller, from the University Hospital of Erlangen, Germany, published the data of an autologous CAR-19 T cell therapy for 15 self-free patients at the American Society of Hematology (ASH), Eight of these SA patients all achieved complete remission after 3 months of treatment, And maintain disease activity therapy (SLEDAI) for SLE as 0. Meanwhile, all 15 patients receiving CART cell therapy completely stopped the immunosuppressants. More importantly, the CRS and ICAN of grade 3 and above were not observed in the 15 patients treated. At present, domestic CART enterprises and foreign head MNC such as Novartis and BMS have begun to layout and carry out CAR-T therapy for SLE and other autoimmune diseases, and observed a preliminary efficacy response.

This study in Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology included 5 patients with relapsed and refractory AQP 4 positive NMOSD and 5 patients with multiple myeloma, all patients were treated with Iolensense injection. The investigators performed a single-cell multi-omics analysis of patients' blood and cerebrospinal fluid samples to investigate the in vivo properties of CAR T cells in patients with autoimmune diseases.

 The study found that only 13% of the B cell immunoglobulin heavy chain variable region (IgVH) sequence existed in the peripheral blood and CSF of NMOSD patients, indicating that B cells in the CSF mostly originate from intrinsic B cells in the central nervous system, but not from peripheral blood. CAR T cells with chemotaxis characteristics can penetrate the blood and brain barrier and enter the center, directly kill the abnormal plasma cells of the central nervous system, reduce the secretion of intrathecal autoantibodies and the abnormal activation of immune cells, thus correcting the immune disorder state of the central nervous system in NMOSD patients, which is conducive to the central immune reconstruction of patients.

 We have shown that CAR T cells in immune disease patients are dominated by the cytotoxic CAR T cell phenotype of CD8 +, and that CAR T cell killing is reduced compared with matched controls. The above characteristics explain the relatively mild severity of CRS after CAR-T treatment and the relatively short duration of CAR-T cells, which facilitates the early immune reconstruction of patients, and further confirms the good safety of iolenssay injection in autoimmune diseases.

Bangyao Biology (BRL Medicine) announced that the research results of its new generation of universal CAR-T therapy TyU 19 for the treatment of autoimmune diseases were published in the international top international academic journal Cell. The analysis showed that TyU 19 was able to drain B cells in three patients with refractory autoimmune disease within two weeks and reversed extensive fibrotic damage in organs in two patients with diffuse cutaneous systemic sclerosis (SSc). According to the press release, TyU 19 is the world's first allogeneic universal CAR-T therapy to achieve positive results in the treatment of autoimmune diseases.

 The published trial is an investigator-initiated study to evaluate the efficacy and safety of TyU 19 in the treatment of patients with recurrent or refractory autoimmune diseases, and is expected to recruit patients with systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, inflammatory myopathy, ANCA related systemic vasculitis, antiphospholipid syndrome. In the results presented here, one patient with refractory immune-mediated necrotizing myopathy (IMNM) and two patients with systemic sclerosis received a single infusion of TyU 19.

 Using healthy donor-derived T cells, the team prepared a generic targeted CAR-T cell drug (TyU 19) for B lymphocyte CD19, realizing the mass production of CAR-T cells and meeting the ready use of CAR-T cell therapy.

Analysis revealed that CAR T cells persisted in the patient after infusion over 3 months and complete B cell depletion was achieved within 2 weeks. During the 6-month follow-up period, all three patients achieved deep disease remission by analysis of clinical remission index scores for both diseases.

The IMNM subject was a 42-year-old female. Imaging and pathological examination showed significant resolution of muscle inflammation and improvement in severe skeletal muscle injury after TyU 19 treatment, with her total improvement score (TIS) rising rapidly (at 2 months) from 72.5 to 100 at baseline and maintaining this level throughout the subsequent follow-up period.

Two other subjects with severe systemic sclerosis had significantly higher CRISS scores within months after receiving TyU 19 cells and modified Rodnan skin scores (mRSS) in both patients. In addition, the fibrosis damage of important organs was also reversed and improved continuously during the 6-month monitoring period. The entire treatment course was well tolerated, with no cytokine release syndrome (CRS), graft-versus-host disease (GvHD), or immune effector cell-associated neurotoxicity syndrome (ICANS) being observed in all three patients

Both IMNM and SSc patients receiving TyU 19 achieved remission

brief summary:

CAR T cell therapy in the treatment of autoimmune diseases, But as with CAR-T for hematological tumors, The development process is bound to face efficacy, The influence of safety, price (compared to existing self-free drugs), of course, In terms of efficacy, if long-term follow-up can prove more effective and safe than existing treatments, Favoring refractory autoimmune diseases, Then the price issue can be temporarily ignored, Of course, we prefer to see CAR-T be used less in cancer-autoimmune diseases, This solves a world-class disease treatment problem.

The company's product recommendation

1.103-83-3  https://www.bicbiotech.com/product_detail.php?id=5329

2.17159-80-7  https://www.bicbiotech.com/product_detail.php?id=5330

3.13939-06-5  https://www.bicbiotech.com/product_detail.php?id=5331

4.10210-68-1  https://www.bicbiotech.com/product_detail.php?id=5332

5.15243-33-1  https://www.bicbiotech.com/product_detail.php?id=5333