RESUMO
Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.
Assuntos
Autoimunidade , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autoimunidade/imunologia , Sistema Nervoso Central/imunologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/terapia , Receptores de Antígenos Quiméricos/imunologia , Análise de Célula ÚnicaRESUMO
B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8+ Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.
Assuntos
Mieloma Múltiplo , Miastenia Gravis , Humanos , Imunoterapia Adotiva , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Antígeno de Maturação de Linfócitos B/genética , Linhagem da Célula , Miastenia Gravis/terapia , Linfócitos T , Imunoglobulina GRESUMO
Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.
Assuntos
Doenças Autoimunes , Mieloma Múltiplo , Doenças Musculares , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B , Doenças Neuroinflamatórias , Imunoterapia Adotiva , Doenças Autoimunes/terapia , Autoanticorpos , Doenças Musculares/terapia , Análise de Célula Única , Terapia Baseada em Transplante de Células e Tecidos , Microambiente TumoralRESUMO
Chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) have great potentials in autoimmune diseases and could be novel therapeutics for relapsed/refractory neuromyelitis optica spectrum disorder (NMOSD). To evaluate the safety and efficacy of the CT103A, a self-developed BCMA-targeting CAR construct against BCMA, in patients with AQP4-IgG seropositive NMOSD, an ongoing, investigator-initiated, open-label, single-arm, phase 1 clinical trial is conducted at our center. In total, 12 patients were administered with a CAR-BCMA infusion. Ten of the 12 patients dosed were women (83.3%), with a median age of 49.5 years (range, 30-67). were The most common events of grade 3 or higher were hematologic toxic effects. Seven patients (58%) developed infections, but no grade 4 infections occurred. Cytokine release syndrome was reported in all patients with only events of grade 1 or 2 observed. During the follow-up of a median 5.5 months, 11 patients had no relapse; all patients generally reported improvement in disabilities and quality-of-life outcomes; 11 patients' AQP-4 antibodies in serum showed a downward trend by the cutoff date. CAR T-cell expansion was associated with responses, and persisted more than 6 months post-infusion in 17% of the patients. In summary, CAR T-cell therapy shows a manageable safety profile and therapeutic potentials for patients with relapsed/refractory AQP4-IgG seropositive NMOSD. Another expansion phase is currently underway to determine the safety and efficacy of CAR T-BCMA infusion in patients with other neuro-inflammatory diseases.
Assuntos
Imunoterapia Adotiva , Neuromielite Óptica , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Imunoterapia Adotiva/efeitos adversos , Neuromielite Óptica/terapia , Neuromielite Óptica/etiologia , Imunoglobulina GRESUMO
RATIONALE AND OBJECTIVE: Drug cues can induce craving for drugs of abuse. Dysfunctional regulation of emotion and motivation regarding rewarding objects appears to be an integral part of addiction. It has been found that cognitive strategies decreased the intensity of craving in addicts. Reappraisal strategy is a type of cognitive strategy that requires participants to reinterpret the meaning of an emotional situation. In addition, studies have found that activation of the dorsal anterior cingulate cortex (dACC) is associated with the selection and application of cognitive reappraisal. In present study, we sought to determine whether such cognitive regulation engages the dACC and improves inhibition of craving in smokers. METHODS: Sixteen smokers underwent functional magnetic resonance imaging (fMRI) during performance of a cigarette reward-conditioning procedure with cognitive reappraisal. We focused our analyses on the dACC as a key structure of cognitive control of craving. Cue induced craving under different conditions was obtained. Correlational analysis between the functional response in the dACC and the subjective craving was performed. RESULTS: We found that using a cognitive reappraisal was successful in decreasing the conditioned craving. Right dACC (BA 24/32) engaged in the cognitive reappraisal. In addition, the individual's subjective craving was negatively correlated with the right dACC activation. CONCLUSIONS: These findings suggest that the dACC are important substrates of Inhibition of cue induced craving in smokers. Cognitive regulation by cognitive reappraisal may help addicted individuals avoid the anticipated situations where they are exposed to conditioned cues.