Explore the vast range of titles available.

Objective We report the 12‐month follow‐up outcomes from a Phase 2 clinical trial (NCT04146051) evaluating Descartes‐08, a BCMA‐directed RNA chimeric antigen receptor T‐cell (rCAR‐T) therapy for refractory generalized myasthenia gravis (MG). These findings provide insight into the potential applicability of BCMA‐targeted rCAR‐T therapy for antibody‐mediated autoimmune diseases. Methods In the Phase 2a part of the study, Descartes‐08 was administered at 52.5 × 106 CAR+ cells/kg per infusion with varying dosing frequencies as an outpatient treatment and without lymphodepletion chemotherapy. A subset of participants received Descartes‐08 as six weekly infusions and were followed long term with assessments conducted at 2, 3, 6, 9, and 12 months. Results All seven participants who received six weekly infusions of Descartes‐08 exhibited clinically meaningful improvement in common MG severity scales (MG Composite, MG Activities of Daily Living, Quantitative MG scores, and Quality of Life 15‐revised) at Month 3 without significant toxicity. At Month 9 follow‐up, all participants continued to experience marked clinically meaningful improvements. Five out of seven participants maintained the response at Month 12. A third participant experienced a relapse approximately 6 months after completing on‐study follow‐up. All three participants who experienced loss of clinical effects were retreated. Two had rapid improvement in clinical scores with minimal symptom expression at Week 8, which was maintained through 12 months of retreatment follow‐up. The third participant experienced similar improvement in MG severity scores to their initial treatment. Interpretation These data support continued development of Descartes‐08 in myasthenia gravis and other autoantibody‐associated autoimmune disorders.

Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)—rather than the conventional DNA approach—to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III–IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II–IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3–9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were –6 (95% CI –9 to –3) for MG-ADL score, –7 (–11 to –3) for Quantitative Myasthenia Gravis score, –14 (–19 to –9) for Myasthenia Gravis Composite score, and –9 (–15 to –3) for Myasthenia Gravis Quality of Life 15-revised score. In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

Andrew Feinberg, Christine Iacobuzio-Donahue and colleagues describe the epigenomic reprogramming that occurs during pancreatic cancer progression. They also show that hematogenous metastases co-evolve a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP) and that oxPPP inhibition reverses chromatin reprogramming and blocks tumorigenic potential. During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis. Changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin histone H3 lysine 9 (H3K9)-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed reprogrammed chromatin, malignant gene expression programs, and tumorigenesis. These findings suggest a model whereby linked metabolic–epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.

This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.

BackgroundThe thalamus is a key grey matter structure, and sensitive marker of neurodegeneration in multiple sclerosis (MS). Previous reports indicated that thalamic volumetry using artificial intelligence (AI) on clinical-quality T2-fluid-attenuated inversion recovery (FLAIR) images alone is fast and reliable.ObjectiveTo investigate whether thalamic volume (TV) loss, measured longitudinally by AI, is associated with disability progression (DP) in patients with MS, participating in a large multicentre study.MethodsThe DeepGRAI (Deep Grey Rating via Artificial Intelligence) Registry is a multicentre (30 USA sites), longitudinal, observational, retrospective, real-world study of relapsing-remitting (RR) MS patients. Each centre enrolled between 30 and 35 patients. Brain MRI exams acquired at baseline and follow-up on 1.5T or 3T scanners with no prior standardisation were collected. TV measurement was performed on T2-FLAIR using DeepGRAI, and on two dimensional (D)-weighted and 3D T1-weighted images (WI) by using FMRIB’s Integrated Registration and Segmentation Tool software where possible.Results1002 RRMS patients were followed for an average of 2.6 years. Longitudinal TV analysis was more readily available on T2-FLAIR (96.1%), compared with 2D-T1-WI (61.8%) or 3D-T1-WI (33.2%). Over the follow-up, DeepGRAI TV loss was significantly higher in patients with DP, compared with those with disability improvement (DI) or disease stability (−1.35% in DP, −0.87% in DI and −0.57% in Stable, p=0.045, Bonferroni-adjusted, age-adjusted and follow-up time-adjusted analysis of covariance). In a regression model including MRI scanner change, age, sex, disease duration and follow-up time, DP was associated with DeepGRAI TV loss (p=0.022).ConclusionsThalamic atrophy measured by AI in a multicentre clinical routine real-world setting is associated with DP over mid-term follow-up.

During the evolutionary progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death1–3. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones1. This raises the possibility than an epigenetic process might operate during metastasis. Here we detected striking epigenetic reprogramming of global chromatin modifications during the natural evolutionary history of distant metastasis. Genome-wide mapping revealed that global changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin K9-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed malignant chromatin and expression states and blocked tumorigenicity. This suggests a model whereby linked metabolic-epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.

xxx