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Key Points Although immunosuppressive therapy is effective at present, toxicity remains an important problem. Many of the existing immunosuppressive agents are directed against ubiquitous targets and therefore have side effects that are unrelated to immunosuppression. Consequently, generating drugs against molecules with restricted expression and/or function might be advantageous. The Janus kinase JAK3 is crucial for signalling by key immunoregulatory cytokines, but has restricted expression and function. This is best illustrated by patients with mutations of the gene encoding this kinase: such children have severe combined immunodeficiency but do not have abnormalities outside of the immune system. This phenotype suggests that JAK3 might be an ideal target. A selective JAK3 inhibitor, CP-690,550, has now been generated to effectively block immune responses both in vitro and in vivo . Other JAK3 inhibitors have been previously described, but none are as potent or selective as CP-690,550. This drug is effective in models of transplant rejection and is not associated with the toxicities that are seen with other immunosuppressive agents. A JAK3 inhibitor is likely to have uses in many settings beyond transplantation, including autoimmune disease and possibly haematopoietic malignancy. Targeting other JAKS and other elements in the JAK/STAT pathway is also conceptually appealing. On the basis of the phenotype that is associated with TYK2 deficiency, a TYK2 antagonist might be useful in inhibiting diseases that are characterized by the activation of T H 1 cells. Given their importance in malignant transformation and immunoregulation, STAT proteins have received considerable attention as therapeutic targets and STAT inhibitors are being studied at present. SOCs proteins are cytokine-induced feedback inhibitors of signalling, which can also be considered as potential targets. Thousands of organs are transplanted each year and millions of people suffer from autoimmune diseases, which creates a need for an armamentarium of immunosuppressive drugs. Unfortunately, immunosuppressants have unwanted side effects owing, in part, to the fact that they have ubiquitous molecular targets. Cytokines have emerged as important controllers of the immune response, and work during the past decade has identified Janus kinases (JAKs) and signal transducers, and activators of transcription (STATs), as crucial intracellular elements in cytokine signalling. Here, we discuss the potential of the JAK/STAT pathway as a target for new immunosuppressants. In particular, the inhibition of JAK3 seems to be an excellent strategy, because of the selective expression and precise functions of this kinase.

ObjectiveTo evaluate the safety and efficacy of CD19 chimeric antigen receptor (CAR) T cell therapy in a patient with refractory lupus nephritis who experienced severe disease flare during immunosuppressive washout, and to assess whether pulse corticosteroid intervention affects CAR T cell therapeutic outcomes.MethodsWe report a single case of a 22-year-old woman with SLE and lupus podocytopathy refractory to multiple therapies including rituximab, belimumab and obinutuzumab. The patient was treated under single-patient IND (#30146) with autologous CD19 CAR T cells (KYV-101). During the preinfusion washout period, she developed severe lupus flare requiring pulse intravenous methylprednisolone. Clinical outcomes, CAR T cell expansion, B cell depletion and laboratory parameters were monitored before and after therapy.ResultsDespite experiencing severe lupus flare (fever, rash, arthritis, anti-dsDNA elevation, hypocomplementaemia) during washout, pulse methylprednisolone (250 mg intravenous, rapidly tapered) successfully controlled symptoms without compromising subsequent CAR T cell expansion (peak 15.5 cells/µL on day 7). The patient achieved sustained clinical remission with SLE Disease Activity Index Score decreasing from 17 prior to leukapheresis to 4 by week 17. At 12 months postinfusion, she remained in drug-free remission with stable kidney function and had returned to full-time work.ConclusionThis case report illustrates that targeted pulse corticosteroids during CAR T cell therapy washout can effectively manage severe lupus flares without impairing therapeutic efficacy.

Infusion of T cells engineered to express chimeric antigen receptors (CARs) that target B cells has proven to be a successful treatment for B cell malignancies. This success inspired the development of CAR T cells to selectively deplete or modulate the aberrant immune responses that underlie autoimmune disease. Promising results are emerging from clinical trials of CAR T cells targeting the B cell protein CD19 in patients with B cell-driven autoimmune diseases. Further approaches are being designed to extend the application and improve safety of CAR T cell therapy in the setting of autoimmunity, including the use of chimeric autoantibody receptors to selectively deplete autoantigen-specific B cells and the use of regulatory T cells engineered to express antigen-specific CARs for targeted immune modulation. Here, we highlight important considerations, such as optimal target cell populations, CAR construct design, acceptable toxicities and potential for lasting immune reset, that will inform the eventual safe adoption of CAR T cell therapy for the treatment of autoimmune diseases.Recent clinical studies show that chimeric antigen receptor (CAR) T cells, best known for treating B cell malignancies, can be used to treat patients with various B cell-driven autoimmune diseases. Here, the authors update us with the progress so far and the considerations for further improving and extending their therapeutic application.

Building upon a study published in The Lancet Neurology showing the feasibility of transiently expressed B-cell maturation antigen (BCMA)-targeted RNA chimeric antigen receptor (CAR) T-cell therapy in patients with myasthenia gravis,1 we report a case that indicates that a different CAR T-cell approach that targets CD19 with a stably expressed CAR, delivered following a conventional lymphodepleting regimen, might be safe and effective in the treatment of severe and refractory myasthenia gravis. Previous treatment attempts, including thymectomy (in April, 2022, performed at another academic centre), acetylcholinesterase inhibitors (initiated in 2012 at our institution), and B-cell-depleting antibodies (rituximab, administered in April and October, 2021, at our institution) did not stabilise the disease course, which was class V according to the Myasthenia Gravis Foundation of America criteria (defined as intubation, with or without mechanical ventilation, except when used during routine postoperative management).3 Moreover, a proteasome inhibitor (bortezomib, administered in May and November, 2022), immunosuppressive drugs (mycophenolate mofetil, administered for 21 months preceding the CAR T-cell infusion), and immunoglobulin therapy (initiated in October, 2021) had proven futile in providing long-term relief (appendix p 4). The serological findings were paralleled by the patient's improved muscle strength and fatigue over the first 2 months after CD19 CAR T infusion, evidenced by the steady increase in the time that the patient could hold out her arm horizontally, her enhanced walking ability without any supportive devices, and the reduction of the clinical multiparameter Besinger disease activity and the Quantitative Myasthenia Gravis scores3,8 (figure).

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO(+)CD62L(-) effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant.

Severe autoimmune-mediated neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and paranodopathies, often remain refractory to established immunotherapies. 1–3 Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promising therapeutic potential in autoimmune conditions through substantial and sustained B-cell depletion. 4,5 Here, we report treatment of two patients with severe, treatment-refractory autoimmune neuropathies using autologous anti-CD19 CAR T cells ( appendix pp 2–3). In March, 2023, the patient first presented to our university hospital with rapid progression to symmetric tetraplegia despite extensive immunotherapy (intravenous immunoglobulin, corticosteroids, plasmapheresis, cyclophosphamide, rituximab, obinutuzumab, and bortezomib; appendix pp 4–6). JM declares stock ownership from Amgen, Bayer, and Sanofi; travel grants from Alnylam, Biogen Idec, Novartis, Teva, Eisai, Neuraxpharm, Bristol Myers Squibb, and Kyverna; consulting fees from Novartis and Alnylam; and research funding from Klaus Tschira Foundation, Ruhr-University Bochum (FoRUM program), Deutsche Multiple Sklerose Gesellschaft, Hertie Foundation, Novartis, and Kyverna, not related to this work.

The annualised incidence of primary immune thrombocytopenia is approximately 3·3 cases per 100 000 people among adults. 1 Despite several treatment options, including approved thrombopoietin receptor agonists and commonly used antibody-reducing approaches—such as B-cell depletion with the anti-CD20 monoclonal antibody rituximab, BTK inhibitors, SYK inhibitors, corticosteroids, and splenectomy—a subset of patients develop refractory immune thrombocytopenia. 2 For these individuals, who are estimated to comprise less than 10% of the total immune thrombocytopenia population, conventional therapies do not achieve durable platelet recovery, resulting in life-threatening bleeding episodes and substantially impaired quality of life. In April, 2024, after a case review by an independent interdisciplinary committee, the hospital board, and the hospital's legal department, the patient gave written informed consent to receive autologous CD19 CAR T-cell therapy as an individualised treatment under German law, which allows the use of unlicensed therapies ( appendix p 1). Within the reconstituting B cell compartment, we observed predominantly CD21 + CD27 – naive cells, with low to absent (switched or non-switched) CD21 + CD27 + memory B cells and CD38 + CD20 – plasmablasts ( figure D), which is also consistent with previous data in patients with autoimmune diseases receiving CAR T cells. 3,9 To avoid withdrawal effects after stopping thrombopoietin receptor agonist, romiplostim treatment, which had been interrupted since day –9, was resumed on day 16 after infusion. Pathogenic autoantibodies against glycoprotein IIb/IIIa were no longer detectable after day 42 ( appendix p 8). [...]the patient's chronic fatigue had resolved 3 months after treatment, and he was planning to return to work in December, 2024.

The purpose of this study was to predict a safe starting dose of AMG 181, a human anti‐ α 4 β 7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic ( PK ) and pharmacodynamic ( PD ) data. A two‐compartment model with parallel linear and target‐mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK . An E max PD model was used to relate AMG 181 concentration and free α 4 β 7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg −1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α 4 β 7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day −1 and 2900 mL, respectively. The estimated EC 50 for free α 4 β 7 receptor was 14 ng·mL −1 . At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α 4 β 7 receptor EC 10 . Predictions for both C max and AUC matched with those observed in the first‐in‐human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone. e00098