introduce
Autoimmune diseases are a heterogeneous group of diseases characterized by disruption of immune tolerance, sensitization to antigens leading to the formation of autoreactive T and B cells, as well as autoantibodies that trigger organ damage (Figure 1). The types of autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, pemphigus, and multiple sclerosis. In all autoimmune diseases, autoreactive B cell clones and autoantibodies against the patient's autoantigens are formed before the onset of clinical symptoms, while chronic inflammation such as psoriasis, Crohn's disease or ankylosing spondylitis has no B cell-mediated pathophysiological processes and, therefore, is not an autoimmune disease.
In January 2023, "Cell Talk" detailed the major progress of CD19 CAR-T cells in treating the autoimmune disease —— systemic lupus erythematosus.
In September 2023, the Lancet published a review entitled "CART-cell therapy in autoimmune diseases". Based on the literature of CAR-T and self-immunity published between January 2010 and December 2022, the significance of chimeric antigen receptor (CAR) T cells in the treatment of immune, autoimmune diseases.
▲ Figure 1: Autoimmune loop triggers chronic inflammation and tissue damage.
The current management of autoimmune diseases
Autoimmune diseases are usually not chronic and can cause organ damage without therapeutic intervention. Autoimmune T cells and B cell clones trigger disease by inducing autoantibodies, used as effectors that drive target cell lysis (e. g., autoimmune hemolytic anemia), mediate cell activation (e. g., Graves' disease), interfere with cell recognition (e. g., pemphigus), or cause the formation of immune complexes and inflammation (e. g., systemic lupus erythematosus).
Traditional immunosuppressants (e. g., azathioprine) and calcineurin inhibitors (e. g., cyclosporin) are widely used in the treatment of autoimmune diseases. Furthermore, other targeted agents that block the migration of T cells into inflammatory sites, such as natalizumab and vedolizumab, and drugs that regulate the sphingin-1 phosphate receptor, have been developed to treat autoimmune diseases. These drugs usually reduce the inflammatory process, but require treatment for years or even for life; even if remission is achieved, the disease often frequently when immunosuppression stops. Autoimmune diseases caused by immunosuppressants, also require the additional use of glucocorticoids to suppress inflammation, which can cause considerable side effects.
Selective interference with B cell activation and autoantibody production in autoimmune diseases is a promising therapeutic approach. The breakthrough work came from the 2004 discovery by Edwards and colleagues that the removal of B cells using rituximab was effective in treating rheumatoid arthritis; however, a randomized controlled trial of rituximab in the treatment of systemic lupus erythematosus did not show clinically or statistically significant results in the disease improvement.
The current limitations of B cell-targeted therapy and the concept of deep B cell clearance in autoimmunity
Control of autoimmune diseases, as well as underlying immune resetting, may require deep clearance of B cells.rituximab through antibody-dependent cytotoxicity does not completely remove circulating B cells because effector cells are not always present and low antibody concentrations may lead to insufficient clearance of target cells; some studies have also shown that memory B cells can escape rituximab clearance. Moreover, B cells can be detected in the synovium when peripheral B cells are cleared. Thus, clearance of tissue-resident B cells has a greater challenge compared to circulating B cells, suggesting that memory B cells in the tissue may be more resistant to clearance. In addition, post-hoc analysis (post-hoc) of some failed clinical studies showed that patients with complete elimination of peripheral B cells respond better to treatment than those with only partial elimination. Another unanswered question is the ideal target antigen. For example, CD20 antigen is not expressed in plasma cells and plasmablasts, while rituximab treatment of SLE in relapse often contains plenty of plasmablasts.
Principles of CAR-T cells targeting B cell-derived malignant tumor cells
Researchers have been trying to permanently stop people with autoimmune diseases from using immunosuppressive drugs by deeply resetting the immune system. For example, starting the immune system with autologous hematopoietic stem cell transplantation (auto-HSCT) after high-dose chemotherapy; however, severe toxicity limits its use in systemic lupus erythematosus. In recent years, cell therapy-based treatment models have experienced rapid development due to the development of genetically engineered receptors such as CAR. DNA encoding CAR can be transferred to in vitro immune cells, such as T cells, to generate CAR-T cells (Figure 2).
▲ Figure 2: Principle of autologous CAR-T cell therapy
After infusion of CAR T cells into the host, these cells recognize antigens, are activated and kill target cells in malignant tumors. To completely clear the tumor to prevent recurrence, targeting hard-to-reach tissue and residding in tumor cells is essential. The applicability of CAR T cells is attributed to the natural ability of T cells to infiltrate the tissue, the high affinity specificity of binding to the target, and their anti-tumor effector function. Upon binding of the target antigen (e. g., the surface molecules CD19, CD20 and CD22 of the B cell lineage) (Figure 3) to the CAR expressed on the T cell or NK cell membrane, the CAR-T / CAR-NK cells are activated and subsequently the tumor cells are killed. Ideally, CAR-expressing cells can survive in tissues for many years by forming a memory phenotype.
▲ Figure 3: Surface antigen expressed by the B-cell lineage
Currently, CAR T cells have become a powerful tool for cancer therapy to deeply and continuously eradicate cells expressing target antigens. CAR-T therapy for B cell malignancies provides long-term remission in up to 50% of patients. However, there are some limiting factors in CAR T cell therapy, such as tumor recurrence and toxic effects due to immune escape.
Cytokine release syndrome (CRS) is a common toxicity of CAR T cell therapy, with mild symptoms of fever, headache, arthralgia, and myalgia, severe hypotension and even cytotoxic shock, ranging from 42% to 93%, and life-threatening events. Another typical side effect is the immune effector cell-related neurotoxicity syndrome (ICANS), which can be manifested as dysgrapia and aphasia, headache, confusion, seizures and behavior changes. The occurrence of ICANS may be related to the activation of endothelial cells and the destruction of the blood-brain barrier. Treatment of these two toxic side effects usually uses antipyretics, glucocorticoids, and IL-6 monoclonal antibodies.
Autoimmune diseases may benefit from CAR-T cell therapies
Theoretically, autoimmune diseases can be treated with CAR T cells that recognize B cell-specific surface molecules. However, apart from forming autoantibodies, the pathophysiological role of B cells in individual autoimmune diseases is not fully understood. B cell activation and autoantibody formation may also be simply a phenomenon in T cell-mediated autoimmunity rather than a cause of initiating disease. In this case, even complete B cell clearance may not be an effective treatment, as the remaining autoreactive T cells would still maintain the disease state.
At the same time, the clinical symptoms of autoimmune diseases may not only originate from persistent inflammation, but may also be the result of permanent organ damage, so that the reversibility of symptoms even after CAR T cell treatment is successful. For example, renal damage in systemic lupus erythematosus, pulmonary fibrosis in systemic sclerosis, muscle atrophy in myositis, secretory gland fibrosis in Sjogren's syndrome, etc. Thus, the early use of CAR T cells may become particularly important in the treatment of autoimmune diseases to avoid missing the window of opportunity for symptom reversibility and to minimize the risk of permanent organ damage.
Preclinical studies have shown that CD19 CAR-T cells eliminate abnormal B cell immune responses in autoimmune diseases and reduce inflammation in organs (such as the kidney) in a mouse model of systemic lupus erythematosus. However, CAR-T cells present some challenges in treating patients with autoimmune diseases. First, patients with autoimmune diseases usually use both glucocorticoids and other drugs (such as mycohenolate or cyclophosphamide) that affect the quantity and quality of T cells, increasing the difficulty of extracting and expanding sufficient functional T cells from patients; second, the T cell components of patients with autoimmune diseases contain autoreactive T cell clones that may also be expanded during the manufacture of CAR T cells. Indeed, backtransfusion of CAR T cells carrying autoimmune T cell receptors may aggravate autoimmune disease.
CD19 CAR-T cells, first used in 2021 to treat a 20-year-old woman with severe refractory systemic lupus erythematosus, showed that producing CAR T cells from patients with autoimmune disease was feasible, and that the patient was well tolerated by CAR-T cell infusion without causing any severe toxic effects. This treatment enables a rapid clearance of B cells in vivo, accompanied by a rapid expansion of CAR T cells in the peripheral blood. The patient's symptoms resolved after 3 months, including resolution of proteinuria, and a seroconversion of disease-associated antibodies against double-stranded DNA was observed. In addition, all immunosuppressive agents (including glucocorticoids) were withdrawn and had no signs of disease recurrence within 18 months.
Then in 2022, a deeper clinical study of CD19 CAR T cells for SLE was reported in five patients with severely resistant SLE, and it showed that despite T cell targeted drugs (the use of mycohenolate or glucocorticoids) as the previous treatment, the production of CAR T cells did not appear to affect the production of T cells. Furthermore, CAR T cells expanded in vivo at similar times in these patients and peaked approximately 1 week after administration (Figure 4).
▲ Figure 4: Stage and challenge of autologous CAR-T cell therapy to treat autoimmune diseases
At the same time, the clinical symptoms of five patients with rapid relief, the relief is accompanied by several systemic lupus erythematosus related antibodies (such as double-stranded DNA, nucleossome and Smith antigen antibodies) seroconversion, but the long-standing vaccine immune response (such as measles, rubella and tetanus vaccine immune response) mostly remain stable or only slightly decreased. The above results indicated that at least some of the autoantibodies in the patients were from CD19-positive memory B cells and plasmablasts, while antibodies against the vaccine were mainly from CD19-negative plasma cells.
Another key finding of CAR T cells in patients with systemic lupus erythematosus is that patients do not have long-term B cell loss because B cells undergo reconstitution approximately 100 days after infusion. Analysis of these B cells showed that memory B cells and plasmablasts almost disappeared and newly emerged B cells display an initial phenotype expressing IgM and IgD heavy chains. B cell regeneration after CAR-T cell treatment was not associated with disease recurrence because all patients were in treatment-free remission and did not produce double-stranded DNA autoantibodies. CAR T cell therapy was well tolerated without high-grade cytokine release syndrome, neurotoxicity, hematologic toxicity, or infectious complications.
In addition to lupus indications, a patient with severe drug-resistant dermatomyositis (dermatomyositis) has been reported to receive CD19 CAR T cells. After treatment, the patient was in non-therapeutic remission, B cells were deeply removed, creatine kinase concentration normalized, muscle and lung inflammation subsided, and physical function fully recovered. The results of the above clinical studies suggest that the therapeutic effect of CD19 CAR-T cells may not be limited to systemic lupus erythematosus, but may also have a role in several different B cell-mediated and autoantibody-driven human autoimmune diseases.
Time duration and duration of response for CAR T cell activity in autoimmune diseases
The duration of drug-free remission after CAR T cell therapy for autoimmune diseases remains to be determined, and the disease-free observation period of some SLE patients reaches 2 years. Therefore, CAR T cell therapy is a very promising cure for autoimmune diseases, but long-term follow-up is still needed. Because newly generated B cells mature at the time of infection and vaccination, it is important to know whether this maturation process is accompanied by the formation of autoreactive B cell clones, autoantibodies, and ultimately by the recurrence of the disease.
CAR T cells need to have the potential to survive for years in vivo. However, sustained and stable regeneration of B cells in patients with autoimmune diseases treated with CAR T cell therapy indicates a low probability of long-term presence of CAR T cells, suggesting the occurrence of cell contraction, as well as activation-induced cell death or depletion. One reason may be that patients with autoimmune diseases receive less cytotoxic drugs, and the reconstructed cells may be more successfully competing for some niches (such as bone marrow or lymphoid tissue) than cancer patients; Another possible explanation is that patients with autoimmune diseases have many times lower B cell load than tumor patients, and the loss of the target antigen may trigger early atrophy of the CAR T cell population. However, prolonged B cell depletion may not be desirable in autoimmune diseases because B cells will provide humoral protection and participate in the immune balance.
Challenges in terms of safety and cost-effectiveness
Although gradually increasing mortality in patients with autoimmune diseases, it is substantially lower than that in patients with relapsed or refractory B cell malignancy, life-threatening cytokine release syndrome and neurotoxicity following CAR-T treatment are unacceptable in patients with autoimmune diseases. Therefore, a lower incidence of high-grade adverse effects, including hematotoxicity, low γ -globulinemia, and infectious complications, is crucial for CAR T cells to become an acceptable treatment option in the future.
In patients receiving CAR-T cell therapy for autoimmune disease, treatment was well tolerated and no occurrence of CRS greater than grade 1 (fever) and ICANS was observed. Although this low toxicity may be based on the significantly lower target binding of CAR T cells in autoimmune disease than in B cell malignancies, however, it remains to be confirmed whether the use of glucocorticoid and toezumab during treatment has any negative effects on patients with autoimmune disease.
Given the high cost of manufacturing CAR T cells, this therapy may initially be indicated only to patients with particularly severe autoimmune disease. However, because CAR-T cells allow the withdrawal of all other immunosuppressive medications in patients with SLE, these treatments are associated with considerable cumulative drug costs (up to $100,000 per year), CAR-T cells can actually reach a break-even point within a few years. Therefore, CAR T cells may be cost-effective for the treatment of autoimmune diseases.
Future strategies for CAR-T cell therapy in autoimmune diseases
The feasibility of CAR T cells for autoimmune diseases will largely depend on multidisciplinary cooperation between immunologists, hematologists, and experts in the fields of rheumatology, nephrology, and neurology, and screening suitable patients through specialized medical centers. CD19 appears to be a promising target because it is highly specific for the B cell lineage and widely expressed at different stages of B cell differentiation; CD20 and CD22 may also be target antigens for CAR T cells for SLE, although both are not necessarily better than CD19 because their expression overlaps with CD19 but is less or absent in plasmablasts and plasma cells (Figure 3).
CD38 and BCMA are two antigens expressed in malignant plasma cell diseases, and some forms of systemic lupus erythematosus and other autoimmune diseases may be more plasma cell-dependent and are therefore more likely to benefit from therapies targeting plasma cells than deep B cell (and plasma cell) clearance. CAR T cells, which target both CD19 + B cells as well as CD38 + plasma cells, may play a role in the treatment of autoimmune diseases. However, its safety is unclear, and the characteristics of targeting BCMA CAR T cells in hematological malignancies, including neurocognitive and motor disorders and pulmonary changes, should be considered.
sum up
CAR T cells have been successfully applied in the treatment of autoimmune diseases, the uniqueness of this method, not only because it is complex, personalized transgenic autologous cell products, but also because of its long-term drug-free remission through one-time intervention, this method may indicate a new era of autoimmune disease treatment, the current therapeutic principles of long-term immune suppression into a immune reset strategy that does not need further therapy. The potential application of targeting CAR T cells for autoimmune diseases still needs further investigation and numerous studies are under way and will shed more on the potential of this therapeutic approach.
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