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Cited by 3 publications
References 9 publications
The Future of CAR T Therapeutics to Treat Autoimmune Disorders
The concept of chimeric antigen receptor (CAR) T cell therapy emerged from cancer immunotherapy and has been rapidly adapted and developed for the treatment of autoimmune, especially B-cell-driven, diseases since the first publication of an article featuring a patient with systemic lupus erythematosus in 2021. Phase II studies are about to start, but up to now, only case reports and small series have been published. In contrast to hemato-oncological diseases, where an aggressive response to malignant cells and long-lasting persistence of CAR T cells has been aimed at and observed in many patients, this is not the case with autoimmune diseases but might not be necessary to control disease. Future studies will focus on the optimal target but also on the optimal level of immunogenicity. The latter can be influenced by numerous modulations that affect not only cytokine release but also regulation. In addition, there are potential applications in regulatory cells such as CAR regulatory T cells (Treg). The question of toxicity reduction must also be addressed, as long-term complications such as the potential development of malignant diseases, infections, or cytopenia must be considered even more critically in the area of autoimmune diseases than is the case for patients with oncologic diseases. Alternative antibody-based therapies using the same target (e.g., CD3/CD19 bispecific targeting antibodies) have not been used in these patients and might also be considered in the future. In conclusion, CAR T cell therapy represents a promising therapeutic approach for autoimmune diseases, offering a targeted strategy to modulate immune responses and restore immune tolerance.
The Future of CAR T Therapeutics to Treat Autoimmune Disorders
The concept of chimeric antigen receptor (CAR) T cell therapy emerged from cancer immunotherapy and has been rapidly adapted and developed for the treatment of autoimmune, especially B-cell-driven, diseases since the first publication of an article featuring a patient with systemic lupus erythematosus in 2021. Phase II studies are about to start, but up to now, only case reports and small series have been published. In contrast to hemato-oncological diseases, where an aggressive response to malignant cells and long-lasting persistence of CAR T cells has been aimed at and observed in many patients, this is not the case with autoimmune diseases but might not be necessary to control disease. Future studies will focus on the optimal target but also on the optimal level of immunogenicity. The latter can be influenced by numerous modulations that affect not only cytokine release but also regulation. In addition, there are potential applications in regulatory cells such as CAR regulatory T cells (Treg). The question of toxicity reduction must also be addressed, as long-term complications such as the potential development of malignant diseases, infections, or cytopenia must be considered even more critically in the area of autoimmune diseases than is the case for patients with oncologic diseases. Alternative antibody-based therapies using the same target (e.g., CD3/CD19 bispecific targeting antibodies) have not been used in these patients and might also be considered in the future. In conclusion, CAR T cell therapy represents a promising therapeutic approach for autoimmune diseases, offering a targeted strategy to modulate immune responses and restore immune tolerance.
Fcγ-receptor-IIIA bioactivity of circulating and synovial immune complexes in rheumatoid arthritis
ObjectivePrevious technical limitations prevented the proof of Fcγ-receptor (FcγR)-activation by soluble immune complexes (sICs) in patients. FcγRIIIa (CD16) is a risk factor in rheumatoid arthritis (RA). We aimed at determining the presence of CD16-activating sICs in RA and control diseases.MethodsSera from an exploratory cohort (n=50 patients with RA) and a validation cohort (n=106 patients with RA, 20 patients with psoriasis arthritis (PsA), 22 patients with systemic lupus erythematosus (SLE) and 31 healthy controls) were analysed using a new reporter cell assay. Additionally, 26 synovial fluid samples were analysed, including paired serum/synovial samples.ResultsFor the first time using a reliable and sensitive functional assay, the presence of sICs in RA sera was confirmed. sICs possess an intrinsic capacity to activate CD16 and can be found in both synovial fluid and in blood. In low experimental dilutions, circulating sICs were also detected in a subset of healthy people and in PsA. However, we report a significantly increased frequency of bioactive circulating sICs in RA. While the bioactivity of circulating sICs was low and did not correlate with clinical parameters, synovial sICs were highly bioactive and correlated with serum autoantibody levels. Receiver operator curves indicated that sICs bioactivity in synovial fluid could be used to discriminate immune complex-associated arthritis from non-associated forms. Finally, circulating sICs were more frequently found in SLE than in RA. The degree of CD16 bioactivity showed strong donor-dependent differences, especially in SLE.ConclusionsRA is characterised by the presence of circulating and synovial sICs that can engage and activate CD16.
Immunological effects of CD19.CAR-T cell therapy in systemic sclerosis: an extended case study
Objective The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc. Methods Longitudinal analysis of peripheral blood mononuclear cells from an Scl70 + SSc patient treated with CAR-T cells sampled over 18 months by 29-color spectral flow cytometry, in vitro experiments using sera from patient cohorts. Results In the patient treated with CAR-T cells, the substantial clinical improvement was paralleled by dynamic changes in innate lymphoid cells, namely Fcγ-receptor IIIA-expressing natural killer (NK) cells. NK cells adopted a more juvenile, less activated, and less differentiated phenotype. In parallel, the potency of serum to form Scl70-containing immune complexes that activate Fcγ-receptor IIIA decreased over time. These observations suggested a mechanistic link between reversal of adaptive autoimmunity and recovering Fcγ-receptor IIIA-expressing innate immune cells after CAR-T cell therapy via regressing immune complex activity. Experiments with sera from the non-CAR-T-treated SSc cohort confirmed that Scl70-containing immune complexes activate Fcγ-receptor IIIA-expressing NK cells in a dose-dependent manner, substantiating the relevance of this link between adaptive and innate immunity in SSc. Conclusion This report describes for the first time the phenotypic recovery of innate Fcγ-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fcγ receptor IIIA + cells such as NK cells. Graphical Abstract Proposed mechanism of involvement of NK cells and soluble Immune Complexes (sICs) in disease progression during active autoimmunity in SSc (left) and resolution of fibrosis after deep B cell depletion by CD19.CAR-T cells and disappearance of autoantibodies (right).
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