Key words: CART cell therapy; autoimmune diseases; B cells; treatment strategy; Nature Reviews Rheumatology
In recent years, chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of certain B cell-derived malignancies, using genetic engineering techniques to transform T cells to specifically recognize and remove cells expressing specific antigens. The successful application of CART cell therapy has opened up new approaches to treat autoimmune diseases, especially in targeting B cell-cell-mediated autoimmune diseases, where so-called "immune resetting" by deep depletion of B cells, including autoreactive B cell clones, may restore normal immune function. However, the application of CART cell therapy in autoimmune diseases is still in its infancy and faces many challenges, including how to select the right patients, identifying appropriate targets, assessing efficacy and safety, and managing possible side effects. Moreover, there are individual differences in the response to CART cell therapy among different patients, and some patients may not respond to treatment due to factors such as genetic polymorphisms.
On August 6,2024, Georg Schett and many other research scholars published a research paper entitled Advancements and challenges in CAR T cell therapy in autoimmune diseases in the international famous journal Nature Reviews Rheumatology [1]. This study focuses on the progress and challenges of CART cell therapy in autoimmune diseases, aims to provide clinicians and scientists with an in-depth understanding of the application of CART cell therapy in this field and explore how to optimize treatment strategies to improve efficacy and safety and improve the quality of life of patients.
Main study content and results
1.The rationale of CART cell therapy
CAR T cell therapy is genetically engineered to embed the chimeric antigen receptor (CAR) into immune cells such as T cells, using the extracellular region of CAR to specifically identify the antigen and activate T cells through costimulatory signals in the intracellular region (such as CD28 or 4-1BB and CD3 ζ chains). Current CART cell therapy mainly mainly autologous T cells and CAR introduction by lentiviral vectors.
Several new CART cell therapies under development may have implications for the future treatment of autoimmune diseases. These new approaches include the use of allogeneic CAR expressing cells from healthy donors, cord blood or induced pluripotent stem cells, these "readily available" cells with immediate use. To prevent allogeneic rejection or GvHD, these cells undergo gene editing before application, such as removal of TCR and MHC class I and II genes. Meanwhile, coexpressing NK cell inhibitory ligands such as HLA-E may be required to avoid NK cell-mediated disruption. Although preliminary data support the efficacy and tolerability of allogeneic CAR expressing cells in acute leukemia patients, their use in autoimmune diseases is still being explored.
In addition, ways to improve CAR insertion into effector cells are being explored, including the loading of lipid nanoparticles (LNPs) with CAR-encoding mRNA or CRISPR-Cas 9 gene editing payloads, and the development of in vivo CAR methods to express CAR directly in vivo by injection of "targeted" LNPs. There are also studies to develop new CAR constructs, such as CAAR cells and CATCR cells, as well as "superCAR" systems able to switch targets without the redesign of T cells. Although these new technologies are promising, their efficacy and safety in the treatment of autoimmune diseases remain to be proven.
Figure 1. Carrier constructs used for CART cell generation in autoimmune diseases
Figure 2. Range of treatments based on CAR
2.CAR T cell-mediated B cell depletion after infusion
After infusion of CART cells, they quickly kill and expand the target B cells, effectively penetrating the blood-brain barrier and eliminating B cells deep in the tissue, including autoreactive B cell clones. CART cell therapy removes B cells in tissue, interrupts autoantibody production and antigen presentation, and reduces T cell activation. Although this therapy offers new therapeutic routes for autoimmune diseases, the number of patients currently treated is limited and the treatment process requires multidisciplinary teamwork involving rigorous patient screening, evaluation, and management before and after treatment.
Figure 3. Methods and functional consequences of therapeutic B cell depletion
3.Indications: Select the "right" disease and the "right" patient
So far, CART cell therapy has been used to treat autoimmune diseases including systemic lupus erythematosus (SLE), systemic sclerosis, myasthenia gravis and multiple sclerosis, where B cells and autoantibodies play a central role in pathogenesis. Since CART cells can deeply deplete B cells, including the elimination of autoreactive B cell clones, only diseases truly driven by B cells may respond to this treatment. However, CART cell therapy may be ineffective for chronic inflammatory diseases without significant B cell pathology components, such as psoriasis, inflammatory diseases, bowel disease and ankylosing spondylitis, which may require other cell-based treatment strategies.
CART cell therapy is mainly used to treat severe patients who are resistant to conventional therapy and are at risk of organ failure or death. Despite its sustained suppression of inflammation, its reversal effect is limited in patients who have suffered a greater degree of organ damage. The ideal CART cell therapy patients are those individuals who are resistant to treatment but have less organ damage so that they can receive maximum benefit from the treatment. Currently, clinical trials begin to include patients who have tried at least two immunosuppressive therapies but have not yet exhausted all treatment options, in hopes of early intervention to prevent permanent organ damage. Organ damage should be assessed before treatment to ensure that the patient can withstand potential side effects. If it is positive, it may be considered as an early treatment option in the future, especially for high-risk patients. CART cell therapy may not be preferred for mild to moderate autoimmune diseases. Furthermore, patient vaccination status should be considered before treatment because patients experience impaired vaccine response during B cell deletion.
4.Select the targets for cell therapy
Most CART cell therapies for autoimmune diseases use CART cells targeting CD19, as CD19 is widely expressed during B-cell differentiation and contributes to the depletion of various B cells, including precursors. Although CD19 is expressed on some cells of the CNS, possibly related to neurotoxicity in therapy, it provides a broader range of B cell targeting compared to targeting CD20. BAs another target, BCMA may be particularly useful for those patients who relapse after CD19-targeted therapy. Targeting both CD19 and BCMA or targeting BCMA alone may be suitable in patients where autoantibodies are mainly produced by plasma cells. CD38 is another potential target that is expressed on a variety of cell types, possibly combining the advantage of early B cell depletion and antibody-producing cell targeting. Furthermore, lower B cell plasticity and mutation rates in autoimmune diseases compared to malignancies reduce the risk of immune escape. In the future, CAR Treg cells may provide a new therapeutic strategy, but currently their efficacy remains to be verified.
5.The role of lymphocyte depletion
Lymphocyte depletion is considered a key component of successful CART cell therapy, which promotes (steady state) expansion after antigen recognition by reducing the number of lymphocytes, allowing small numbers of CART cells to expand in vivo and deep depletion of all B cells in the body cavity. Commonly used lymphocyte depletion therapy is a combination of cyclophosphamide and fludarabine, and this regimen is critical for anti-CD19 CAR T-cell therapy in B cell malignancies. Although whether lymphocyte depletion therapy must be required in the treatment of autoimmune diseases is unclear, such a regimen may be required because patients often have an intact, rarely chemotherapy-pretreated, often over-activated T cell system and normal bone marrow cells. Moreover, lymphocyte depletion may also help to reset the immune system, and the deep depletion of T cells in the short term may help to better reconstruct the primitive B cells and part of the T cell immune system. Although lymphocyte depletion therapy may partially support the efficacy of CART cell therapy in the early stages of treating autoimmune diseases, it is unlikely that this approach is to contribute to long-term drug-free remission. Nonetheless, the current data suggest that lymphocyte depletion therapy may be an important component of effective CART cell therapy in autoimmune disease, despite potential dose reduction without compromising the efficacy of autoimmune disease. Importantly, a short-term lymphocyte depletion regimen is not sufficient to explain the sustained medium-and long-term beneficial effects of CART cell therapy.
6.Patient monitoring after CART cell therapy
Long-term follow-up is crucial for patients receiving CART cell therapy, especially those receiving experimental therapy for autoimmune disease. The FDA recommends lifelong monitoring for all patients receiving cell therapy to prevent cytokine release syndrome, neurological and myelotoxicity, and secondary malignancies. The expansion of CART cells is an early indicator of their in vivo functionality and can be detected by flow cytometry or real-time PCR. Regular monitoring of B cells to detect their depletion and recovery is important for assessing treatment efficacy. Furthermore, immunoglobulin levels and vaccine titers need to be monitored to guide the need for immunoglobulin replacement and revaccination. It is also necessary to monitor the dynamics of immune cell subsets, particularly of CD4 T helper cells, to assess the risk of opportunistic infections. Monitoring of autoantibodies is also important to assess disease activity and the clinical impact of treatment. Furthermore, the monitoring of changes in patient quality of life and organ function is also necessary. For all CART cell therapy patients, especially younger patients, long-term or even lifelong monitoring is required to ensure the assessment of the risk of rare events, such as secondary malignancies.
7. Concomitant therapy in the pre, middle and late stages of CART cell therapy
In the context of CART cell therapy, to improve safety and efficacy, concomitant therapies including gradual pering of conventional immunosuppressive therapy before CART cell therapy, managing toxicity during CART cell therapy, and treating potential recurrence after CART cell therapy. Specific measures include: reducing the use of immunosuppressants, Such as cyclophosphamide, mycohenolate mofilic acid, and calcineurin inhibitors, To avoid affecting the manufacturing or quality of CART cell products; During the waiting period between cell collection and treatment, May need to use glucocorticoids as a "bridging" therapy to control autoimmune diseases; For the young female patients, Considering the importance of fertility, Collection and cryopreservation of tissue or eggs may need to be considered; CART cell therapy is often accompanied by anti-infection and seizure therapy, To prevent the neurotoxicity associated with CART cell therapy; After an anti-CD19 CAR T-cell infusion, Inhibition of both B cells and T cells should be avoided, To reduce the risk of opportunistic infections, And before the full recovery of the B cells, Using immunosuppressive agents that may affect T cell function should be avoided. Furthermore, low doses of glucocorticoids do not appear to affect the proliferation and activity of CART cells.
8. Management of disease recurrence
This risk remains, although patients with anti-CD19 CAR T cell therapy have not yet developed recurrence of autoimmune disease. Since therapies act primarily on B cells, it may be unable to remove CD19 negative plasma cells and pathological T cells that produce autoantibodies, thus potentially leading to disease recurrence or drug resistance. Treatment of relapse may require a restart of immunosuppression or a secondary CART cell infusion, depending on the severity of the disease. For example, patients with SLE may refer to existing guidelines, and short-term glucocorticoids may be used for mild recurrence, and other immunosuppressive agents for moderate to severe recurrence. Late relapse may be considered for re-treatment with cryopreserved CART cells, but this may involve additional lymphocyte depletion and associated toxicity. If there is a concern about the immunogenicity of CART cell constructs, fully humanized CART cell constructs may need to be considered. For early relapse, it is possible to explore other CART cell constructs, such as CD38 or BCMA CAR T cells targeting plasma cells. Also, consider whether CART cell therapy improves the sensitivity of patients to conventional therapy.
9. CART cell-associated toxicity
CART cell therapy may trigger short-term toxic responses caused by inflammation and cytokine release, including cytokine release syndrome and other related symptoms. But the lower incidence of these severe toxicities in patients with autoimmune diseases may be related to the lower number of B cells. Treatment was mainly performed with corticosteroids or IL-6 neutralizing antibodies, and patients required close monitoring during the first 10 – 14 days after receiving the infusion. Long-term surveillance is also important to assess the risk of infection, B cell reconstitution, the impact of drug discontinuation on infection risk, and cancer risk. There is currently no evidence that CART cell therapy increases cancer risk, and although the FDA reports cases of T cell lymphoma in patients receiving this therapy, there is no evidence that CART cells directly lead to malignant transformation. Therefore, long-term patient follow-up and risk assessment and in-depth investigation in case of T cell malignancy are needed.
10. Other challenges and considerations
No conclusion of the efficacy and risk of CART cell therapy in autoimmune diseases due to the lack of control group trials. The clinical development path needs to consider the risks and benefits, and may be verified by a single arm study or the establishment of a non-placebo control group. Furthermore, treatment costs and long-term effect observations are essential to assess their economic feasibility and safety.
leaderette:
Clinical significance and scientific research inspiration:
CART cell therapy provides a new therapeutic strategy for autoimmune diseases, but it is still in an early stage. Future studies need to address issues including how to optimize the design of CART cells, improve the safety of therapy, reduce long-term toxicity and how to select appropriate patients. Moreover, more clinical trials are needed to validate the efficacy of CART cell therapy in autoimmune diseases and to explore its applicability in different diseases. With further research, CART cell therapy is expected to be a powerful tool for treating autoimmune diseases.
Expect more similar quality studies to bring better clinical treatment strategies to patients.
Original link:
https://doi.org/10.1038/s41584-024-01139-z
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