B Cell Lineage Reconstitution Underlies Cart Cell Therapeutic Efficacy In Patients With Refractory Myasthenia Gravis Daishi Tian Chuan Qin Minghao Dong Michael Heming Luoqi Zhou Wen Wang Songbai Cai Yunfan You Ke Shang Jun Xiao Di Wang Chunrui Li Min Zhang Bitao Bu Gerd Meyer Zu Hörste Wei Wang by Dai-shi Tian & Chuan Qin & Ming-hao Dong & Michael Heming & Luo-qi Zhou & Wen Wang & Song-bai Cai & Yun-fan You & Ke Shang & Jun Xiao & Di Wang & Chun-rui Li & Min Zhang & Bi-tao Bu & Gerd Meyer Zu Hörste & Wei Wang 101038/S4432102400043Z instant download after payment.

AbstractIntroduction1234567890();,:B-cell maturation antigen (BCMA), expressed in plasmablastsMyasthenia gravis (MG) is a heterogenous autoimmune diseaseand plasma cells, could serve as a promising therapeutic targetcharacterized by muscle weakness and fatigue. Autoreactive B cellsfor autoimmune diseases. We reported here chimeric antigenwith autoantibody formation play a key role in the pathogenesis ofreceptor (CAR) T cells targeting BCMA in two patients with highlyMG, and the autoantibodies in the majority of MG patients arerelapsed and refractory myasthenia gravis (one with AChR-IgG,directed against the muscle acetylcholine receptor (AChR) of theand one with MuSk-IgG). Both patients exhibited favorable safetyneuromuscular junction, while in 6% antibodies against the muscleprofiles and persistent clinical improvements over 18 months.specific kinase (MuSK) are detected (Gilhus, 2016; Gilhus andReconstitution of B-cell lineages with sustained reduced pathogenicVerschuuren, 2015). B-cell maturation antigen (BCMA), primarilyautoantibodies might underlie the therapeutic efficacy. To identifyexpressed in plasmablasts and plasma cells (PB/PCs) at high levelsthe possible mechanisms underlying the therapeutic efficacy of(Mikkilineni and Kochenderfer, 2021), represents a promisingCAR-T cells in these patients, longitudinal single-cell RNA and TCRtarget antigen for novel therapies in autoantibody seropositive MG.sequencing was conducted on serial blood samples post infusionConsidering the pathophysiology of MG, treatment with chimericas well as their matching infusion products. By tracking theantigen receptor (CAR) T cells that recognize BCMA+ B cells mighttemporal evolution of CAR-T phenotypes, we demonstrated thatbe useful in refractory forms of the disease (Verschuuren et al,proliferating cytotoxic-like CD8 clones were the main effectors in2022). Here we present the cases of two refractory MG patients, oneautoimmunity, whereas compromised cytotoxic and proliferationwith AChR-IgG and the other with MuSK-IgG, who received antisignature and profound mitochondrial dysfunction in CD8+ Te cellsBCMA CAR T cells (ClinicalTrials.gov, number NCT04561557). Inbefore infusion and subsequently defect CAR-T cells after manuorder to investigate the evolutionary paths of T cells derived fromfacture might explain their characteristics in these patients. Ourpatients and CAR-T cells in infusion products (IPs), as well as theirfindings may guide future studies to improve CAR T-cell immubehavior after transfer in vivo, we conducted single-cell transcripnotherapy in autoimmune diseases.tomic and T-cell receptor (TCR) sequencing analyses on samples