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The development and successful clinical application of engineered T cells expressing synthetic chimeric antigen receptors (CARs) represents a milestone in cancer therapy. This approach optimizes physiological in vivo T-cell activation against specific target antigens expressed on defined cell subsets with the goal of their deep and sustained depletion. Significant progress has been made in redesigning CAR T-cell constructs to improve patient safety, therapeutic efficacy, and accessibility. Efforts have also focused on streamlining manufacturing to improve availability and reduce costs, two critical challenges to widespread adoption. Beyond hematologic malignancies, CAR T-cell therapies are now increasingly being repurposed to tackle B-cell-mediated autoimmune diseases (AIDs). This is primarily achieved through broad B-cell depletion, but more targeted approaches—such as the selective elimination of autoantibody-producing B-cell subpopulations—are also being explored. Important considerations in their implementation are identifying the most pertinent patient groups, tailoring their treatment up to the point of CAR-infusion, and following up on their unique toxicity-profile. In the context of neurological AIDs—including refractory myasthenia gravis, Lambert–Eaton syndrome, multiple sclerosis, and stiff-person syndrome—early clinical experience suggests promising efficacy and tolerability, leading to a growing number of registered clinical trials. In this review, we provide an overview of the mechanism and evolution of CAR T-cell therapy, highlighting why its application in AIDs, particularly in neurology, represents a highly promising therapeutic strategy. Plain language summary How CAR T-cell therapy could help treat neurological disorders CAR T-cell therapy has revolutionized cancer treatment by engineering a patient’s own immune cells to recognize and destroy harmful cells. Initially developed for blood cancers, this therapy is now being explored for autoimmune diseases, particularly neurological disorders like multiple sclerosis, myasthenia gravis, and stiff-person syndrome. The main way CAR T-cells work in autoimmune diseases is by targeting and eliminating B cells, which play a key role in driving these conditions. Unlike traditional treatments, which often require continuous medication, CAR T-cell therapy has the potential to reset the immune system with long-lasting effects. Early clinical experiences have been promising, showing that CAR T-cell therapy can lead to deep and sustained disease remission. Importantly, the therapy appears to be well tolerated, with fewer severe side effects than in cancer patients. Research is now focusing on optimizing safety, accessibility, and effectiveness to bring this innovative therapy to more patients. By learning from cancer immunotherapy, scientists aim to refine CAR T-cell treatment for neurological autoimmune diseases, potentially offering a transformative new option for patients who have not responded to conventional therapies.

Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis. Short-chain fatty acids (SCFA) are a main class of metabolites derived from fermentation of dietary fibre in the intestine. Here, the authors show that dietary administration of SCFA is associated with inhibition of osteoclast differentiation, increased bone mass, and reduced pathological bone loss in mice.

Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously. Adding to the recent debate on the role of epithelial–mesenchymal transition (EMT) in cancer cell invasion and metastasis, Brabletz and colleagues show that the EMT-inducing transcription factor Zeb1 drives pancreatic tumorigenesis and metastasis.

Autoimmune disorders occur when immune cells go wrong and attack the body’s own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive agents and blocking antibodies, which can manage the diseases but often are not curative. Thus, there is an urgent need for advanced therapies for patients suffering from severe and refractory autoimmune diseases, and researchers have considered cell therapy as potentially curative approach for several decades. In the wake of its success in cancer therapy, adoptive transfer of engineered T cells modified with chimeric antigen receptors (CAR) for target recognition could now become a therapeutic option for some autoimmune diseases. Here, we review the ongoing developments with CAR T cells in the field of autoimmune disorders. We will cover first clinical results of applying anti-CD19 and anti-B cell maturation antigen CAR T cells for B cell elimination in systemic lupus erythematosus, refractory antisynthetase syndrome and myasthenia gravis, respectively. Furthermore, in preclinical models, researchers have also developed chimeric autoantibody receptor T cells that can eliminate individual B cell clones producing specific autoantibodies, and regulatory CAR T cells that do not eliminate autoreactive immune cells but dampen their wrong activation. Finally, we will address safety and manufacturing aspects for CAR T cells and discuss mRNA technologies and automation concepts for ensuring the future availability of safe and efficient CAR T cell products.

BackgroundCD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.MethodsIn this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.ResultsIn a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09).ConclusionsThese data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.

Osteoclasts are specialised bone resorbing cells that control both physiological and pathological bone turnover. Functional changes in the differentiation and activity of osteoclasts are accompanied by active metabolic reprogramming. However, the biological significance and the in vivo relevance of these events has remained unclear. Here we show that bone resorption of differentiated osteoclasts heavily relies on increased aerobic glycolysis and glycolysis-derived lactate production. While pharmacological inhibition of glycolysis did not affect osteoclast differentiation or viability, it efficiently blocked bone resorption in vitro and in vivo and consequently ameliorated ovariectomy-induced bone loss. Our experiments thus highlight the therapeutic potential of interfering with osteoclast-intrinsic metabolic pathways as possible strategy for the treatment of diseases characterized by accelerated bone loss.

Cancer-associated myeloid cells due to their plasticity play dual roles in both promoting and inhibiting tumor progression. Myeloid cells with immunosuppressive properties play a critical role in anti-cancer immune regulation. Cells of different origin, such as tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), myeloid derived suppressor cells (also called MDSCs) and eosinophils are often expanded in cancer patients and significantly influence their survival, but also the outcome of anti-cancer therapies. For this reason, the variety of preclinical and clinical studies to modulate the activity of these cells have been conducted, however without successful outcome to date. In this review, pro-tumor activity of myeloid cells, myeloid cell-specific therapeutic targets, in vivo studies on myeloid cell re-polarization and the impact of myeloid cells on immunotherapies/genetic engineering are addressed. This paper also summarizes ongoing clinical trials and the concept of chimeric antigen receptor macrophage (CAR-M) therapies, and suggests future research perspectives, offering new opportunities in the development of novel clinical treatment strategies.

B-cell development in the bone marrow comprises proliferative and resting phases in different niches. We asked whether B-cell metabolism relates to these changes. Compared to pro B and small pre B cells, large pre B cells revealed the highest glucose uptake and ROS but not mitochondrial mass, whereas small pre B cells exhibited the lowest mitochondrial membrane potential. Small pre B cells from Rag1 −/− ;33.C9 μ heavy chain knock-in mice revealed decreased glycolysis (ECAR) and mitochondrial spare capacity compared to pro B cells from Rag1 −/− mice. We were interested in the step regulating this metabolic switch from pro to pre B cells and uncovered that Swiprosin-2/EFhd1, a Ca 2+ -binding protein of the inner mitochondrial membrane involved in Ca 2+ -induced mitoflashes, is expressed in pro B cells, but downregulated by surface pre B-cell receptor expression. Knockdown and knockout of EFhd1 in 38B9 pro B cells decreased the oxidative phosphorylation/glycolysis (OCR/ECAR) ratio by increasing glycolysis, glycolytic capacity and reserve. Prolonged expression of EFhd1 in EFhd1 transgenic mice beyond the pro B cell stage increased expression of the mitochondrial co-activator PGC-1 α in primary pre B cells, but reduced mitochondrial ATP production at the pro to pre B cell transition in IL-7 cultures. Transgenic EFhd1 expression caused a B-cell intrinsic developmental disadvantage for pro and pre B cells. Hence, coordinated expression of EFhd1 in pro B cells and by the pre BCR regulates metabolic changes and pro/pre B-cell development.

Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.