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iNature
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS) with a recurrent course and severe sequelae
。 The discovery of anti-aquaporin 4 (AQP4) autoantibodies has led to an understanding of its pathophysiology and precise targeting of plasma cells producing immunoglobulin G (IgG) that binds to AQP4 on the optic nerve and spinal cord, leading to a variety of pathological outcomes
.
Chimeric antigen receptor (CAR) T cell therapy targeting B-cell maturation antigen (BCMA) has great potential in autoimmune diseases and may become a new therapy
for relapsed/refractory NMOSD.
On January 4, 2023, the team of Wang Wei of Huazhong University of Science and Technology published an online publication entitled " Anti-BCMA CAR T-cell therapy CT103A in relapsed or refractory AQP4-IgG seropositive neuromyelitis optica spectrum disorders: phase 1 trial interim results To evaluate the safety and efficacy of CT103A, a self-developed CAR construct for BCMA, in patients with AQP4-IgG seropositive NMOSD, the study is conducting an investigator-initiated open-label single-dose phase I clinical trial
.
Studies have shown that CAR-T cell therapy shows controllable safety and therapeutic potential
in 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 neuroinflammatory diseases.
.
However, 25-60% of patients will continue to relapse
.
In recent years, several monoclonal antibodies against different pathophysiological processes have been shown to be effective
in NMOSD treatment.
Among them, monoclonal antibodies against B lymphocytes are considered to have a strong therapeutic effect
on NMOSD.
However, treatment against the B lymphocyte antigen CD20 was not associated with a decrease in serum AQP4-IgG levels and was ineffective in some patients, possibly due to incomplete depletion
of AQP4-IgG.
A new therapy targeting AQP4-IgG-producing cells may be more specific and effective
for AQP4-IgG seropositive NMOSD.
In addition, physical barriers in vivo, such as the blood-brain barrier, can greatly reduce the efficient biodistribution
of monoclonal antibodies in CNS target cells.
CAR-T cell therapy has emerged as an emerging treatment option for long-term disease control of several hematological tumors, and its therapeutic potential has been used to some extent to treat autoimmune diseases such as pemphigus vulgaris and systemic lupus erythematosus (SLE).
。 Compared with monoclonal antibodies, CAR-T cells maintain the same antigen specificity while having multiple advantages of tissue biodistribution characteristics and self-expansion characteristics of cell carriers, B-cell maturity antigen (BCMA) is a member of the tumor necrosis factor superfamily proteins, mainly expressed on
plasma cells and some mature B cells.
The BCMA-targeted CAR construct (CT103A) independently developed by Wang Wei's team showed strong clinical efficacy
after single dose administration of multiple myeloma (MM).
However, CAR-BCMA T-cell therapy has never been reported to treat autoimmune diseases
.
In this study, a total of 12 patients received CAR-BCMA infusion
.
Ten of the 12 patients were female (83.
3%), with a median age of 49.
5 years (30-67 years).
The most common event of grade 3 or higher is hematologic toxicity
.
Figure 1: Flow of the study (from Signal Transduction and Targeted Therapy) The study showed that 7 patients (58%) developed infection but did not develop grade 4 infection
.
Cytokine release syndrome was reported in all patients, with only grade 1 or 2 events
observed.
At a median follow-up of 5.
5 months, 11 patients did not relapse
.
Improvements in disability and quality of life outcomes were generally reported by all patients, with 11 patients showing a downward
trend in serum AQP-4 antibodies to the cut-off date.
CAR-T cell expansion correlated with response, with 17% of patients lasting more than
6 months after infusion.
Figure 2: Functional improvement after CT103A injection (from Signal Transduction and Targeted Therapy).
Taken together, this first-in-human study preliminarily demonstrates that CAR-BCMA T cell CT103A can be used as a safe and potential monotherapy for patients with relapsed or refractory AQP4-IgG seropositive NMOSD and deserves further evaluation in a wider range of applications, particularly in
antibody-mediated autoimmune diseases.
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The content is [iNature]
