CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial.

A bispecific CD3×CD19 antibody for systemic lupus erythematosus: a phase 1 trial

Early-phase studies of deep B cell depletion with anti-CD19 chimeric antigen receptor (CAR) T have produced prolonged, drug-free remission in refractory autoimmune disease. However, CAR T cell therapy requires lymphodepleting chemotherapy, autologous cell manufacturing and specialized infrastructure, limiting reach to a fraction of patients who might benefit. Bispecific T cell engagers (TCEs) offer a potent, off-the-shelf approach to deep B cell depletion; however, controlled clinical evaluation in rheumatic disease remains limited. Here we report results from the intravenous treatment arm of an ongoing, first-in-disease, phase 1 trial of A-319, a next-generation CD3×CD19 TCE, in 12 patients with active systemic lupus erythematosus (SLE) with 52 weeks of follow-up. Patients received A-319 (0.3−1.2 μg kg−1) three times weekly for 3 weeks after 1 week of priming doses (0.05 μg kg−1). The primary endpoint was safety and tolerability. A-319 demonstrated a favorable safety profile, with no treatment-related serious adverse events, deaths, grade 3 or higher cytokine release syndrome (CRS) or neurotoxicity; CRS was predominantly grade 1 (91.6%, 11/12), and hematologic toxicity was minimal. Secondary endpoints (pharmacokinetics, pharmacodynamics and immunogenicity) demonstrated linear pharmacokinetics and dose-dependent B cell depletion, with complete peripheral depletion in higher-dose cohorts. Among exploratory efficacy endpoints, 80% (8/10) of patients achieved Lupus Low Disease Activity State (LLDAS), and 60% (6/10) achieved Definition of Remission in SLE (DORIS) at 12 months, accompanied by sustained reductions in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, autoantibody titers and proteinuria. Exploratory serial single-cell RNA sequencing revealed broad immune reprogramming mechanistically similar to that after CD19 CAR T cell therapy in SLE, including multi-lineage suppression of SLE-associated interferon response signatures across B cell, T cell and myeloid compartments and near-complete reconstitution of the B cell repertoire. Together, these findings demonstrate the feasibility, safety and preliminary efficacy of CD3×CD19 T cell engagement in SLE and support further clinical development of TCEs in controlled, pivotal studies. ClinicalTrials.gov identifier: NCT06400537. In a phase 1 trial evaluating intravenous delivery of a next-generation CD3×CD19 bispecific T cell engager in patients with active systemic lupus erythematosus, treatment was well tolerated, and there were improvements in disease activity scores for most patients.

Long-term outcomes of anti-CD19 CAR T cell therapy in refractory myasthenia gravis: A case series.

Anti-CD19 CAR T cell therapy represents an emerging therapeutic approach for generalized, treatment-refractory myasthenia gravis (MG), a predominantly B-cell-mediated autoimmune disease for which durable treatment-free remission remains an unmet clinical goal. Despite recent advances, current targeted therapies generally require lifelong repeated administration and rarely induce durable treatment-free remission. We report on three patients with severe, treatment-resistant MG, including one patient with concomitant rheumatoid arthritis, treated with autologous, fully human anti-CD19 CAR T cells. All three patients achieve rapid, sustained clinical MG remission for at least 19 months, allowing discontinuation of MG-specific immunotherapies and substantial improvement in clinical and functional outcomes despite persistent detectable anti-AChR autoantibody titers. B cell depletion is profound, and treatment-related adverse events remain transient and manageable during long-term follow-up. These data support anti-CD19 CAR T cell therapy as a durable, effective intervention for refractory MG and warrant further evaluation in prospective controlled clinical trials.

Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome Following Axicabtagene Ciloleucel or Brexucabtagene Autoleucel Chimeric Antigen Receptor T-Cell Therapy: Center for International Blood and Marrow Transplant Research Data.

BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 have demonstrated effectiveness in the treatment of relapsed/refractory B-cell malignancies. Several CAR-T therapies have been approved in the United States, including axicabtagene ciloleucel (axi-cel), for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), and brexucabtagene autoleucel (brexu-cel), for B-cell precursor acute lymphoblastic leukemia and mantle cell lymphoma (MCL). However, use of CAR-T therapies can result in potentially severe adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). OBJECTIVE This analysis of real-world data evaluated the incidence and management of CRS and ICANS in patients with B-cell malignancies following treatment with axi-cel or brexu-cel therapy. STUDY DESIGN This retrospective observational cohort study analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult patients in the United States who received axi-cel or brexu-cel for any indication from October 2020 to December 2021 with ≥1 follow-up visit were included. The main outcome of interest was incidence of CRS and ICANS following CAR-T therapy, graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. Management of CRS and ICANS with preventive therapies and treatments administered following development of CRS and ICANS was also investigated. RESULTS Overall, 927 patients across 87 US centers were included (axi-cel, n=707 [76.3%]; brexu-cel, n=220 [23.7%]). Median (range) age was 63 (19-89) years, and 65.3% (605/927) were male. Most patients (83.3% [n=589]) received axi-cel for diffuse large B-cell lymphoma or transformed follicular lymphoma. All patients who received brexu-cel had mantle cell lymphoma. Overall, 766 (82.6%) patients developed CRS (grade ≥2, 47.0%; 360/766). Of patients with available data, 12.4% (89/715) received CRS preventive therapy, most commonly with tocilizumab alone (79.8%; 71/89). Of patients who developed CRS, 76.6% (587/766) received CRS treatment, including 63.5% (258/406) of patients with grade 1 and 91.4% (329/360) with grade ≥2. The most common treatment was tocilizumab (97.3%; 571/587), alone or in combination. Of patients with available data, 49.8% (356/715) received ICANS prevention, mostly anti-epileptics alone (93.3%; 332/356). Of 876 evaluable patients, 424 (48.4%) developed ICANS (grade ≥2, 71.5%; 303/424). Of these, 85.6% (363/424) received treatment for ICANS, most commonly corticosteroids (92.3%; 335/363). CONCLUSIONS Rates of CRS (82.6%) and ICANS (48.4%) were consistent with incidences expected based on prescribing information for axi-cel and brexu-cel, highlighting potential burdens of CAR-T therapy. These results also stress the importance of continuous patient monitoring and management during CAR-T therapy and demonstrate an evolving treatment landscape, including more aggressive management of CRS and interest in preventive therapies for CRS and ICANS.

Recognition and management of early complications in CAR-T cell therapy and virus-specific T-lymphocyte therapy: a practical clinical reference

Background Cellular immunotherapies—including chimeric antigen receptor T-cell (CAR-T) therapies and adoptive transfer of virus-specific T lymphocytes (VSTs) — have transformed the treatment of refractory hematological malignancies and post-transplant infectious complications. Eight products are currently authorized by the European Medicines Agency, encompassing seven autologous CAR-T products targeting CD19 or BCMA and tabelecleucel (Ebvallo), the first approved allogeneic off-the-shelf EBV-specific T-cell product for EBV-positive post-transplant lymphoproliferative disease. Despite their clinical efficacy, both modalities carry distinct early toxicity profiles that differ from conventional cytotoxic chemotherapy. Objective This review summarizes current recommendations for identifying, assessing, and treating early problems that can occur after CAR-T cell therapy and VST administration. Content CAR-T-specific complications discussed include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and immune effector cell-associated HLH-like syndrome (IEC-HS). CRS is graded by ASTCT consensus criteria and managed with tocilizumab as first-line pharmacological therapy; steroid-refractory ICANS is most commonly treated with high-dose intravenous anakinra (up to 12 mg/kg/day) which is currently the most studied second-line option, although the supporting evidence remains largely observational. ICAHT is classified using the validated EHA/EBMT grading framework, separating early (day 0–30) and late (post-day 30) neutropenia by depth and duration, with management escalating from prophylactic G-CSF through hematopoietic cell boost to allogeneic HSCT as the ultimate option. For VSTs, the principal early complications are tumor flare reaction (in approximately 20% of tabelecleucel recipients), GVHD (below 5% with enriched products), acute infusion reactions, and low-grade CRS-like cytokine release. We summarize a differential diagnosis of overlapping syndromes, pediatric-specific adaptations, ICU escalation criteria, and a clinical monitoring schedule. Conclusions Internationally validated criteria grade the early complications of cellular immune effector therapies. Prompt recognition, early pharmacological intervention, and monitoring are essential to minimize non-relapse mortality. Expanding real-world experience and the integration of pre-treatment risk stratification tools will continue to refine evidence-based practice in this rapidly evolving field, ultimately leading to improved patient outcomes and reduced non-relapse mortality rates.

Immune Profiling after treatment with an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Treatment-Refractory Progressive Multiple Sclerosis

BCMA CAR T-cell therapy in a patient with heavily pretreated relapsed/refractory POEMS Syndrome: a case report

B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T-cell) therapy is an established treatment for relapsed/refractory multiple myeloma. However, its application in POEMS syndrome remains largely unreported, despite overlapping pathogenesis involving plasma cell dyscrasia. Herein, we present a woman in her 30s with heavily pretreated relapsed/refractory POEMS syndrome who received equecabtagene autoleucel, a fully human anti-BCMA CAR T-cell product. The patient achieved a complete vascular endothelial growth factor (VEGF) response by day 14 post-infusion, with sustained remission through 12 months of follow-up. Clinical improvements included resolution of heart failure, pulmonary hypertension, and renal dysfunction, along with marked neurological recovery, enabling the patient to return to normal daily activities and occupational functioning, a status that persisted through the 16-month follow-up. Treatment-related toxicities comprised Grade 2 cytokine release syndrome and persistent hypogammaglobulinemia, without severe infectious complications. No delayed neurotoxicity or secondary malignancies were observed. This case provides evidence that BCMA CAR T-cell therapy is a safe and efficacious option for patients with relapsed/refractory POEMS syndrome.