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Gene & Protein in Disease Review of CAR-T in ADs

The autoantibodies in MG are produced by plasma patients with refractory AQP4-IgG seropositive NMOSD
cells expressing an antigen called BCMA on their surface. successfully enrolled 12 patients and observed only mild
Thus, an mRNA-modified rCAR-T cell therapeutic cytokine release syndrome (CRS) during treatment. During
agent, DesCAR-Tes-08, has been developed to target a median follow-up of 5½ months, serum AQP-4 antibody
BCMA. This agent has shown superior safety and lower levels decreased in 11 patients without recurrence. CAR-T
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toxicity compared with traditional CAR-T cell therapy, cell growth in two patients lasted longer than 6 months.
as mRNA does not replicate and has fewer side effects. Therefore, BCMA CAR-T cell therapy in NMOSD has a
In a clinical trial (MG-001) evaluating the safety and durable therapeutic effect and a tolerable safety profile.
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clinical activity of autologous RNA-CAR-T cells for MG, A clinical trial of BCMA CAR-T cells for the treatment of
DesCAR-Tes-08 significantly improved clinical symptoms other neuroinflammatory diseases is underway.
and demonstrated safety in patients with MG. Notably,
two patients achieved independence from intravenous 3.6. Application of CAR-T cells in the treatment of RA
immunoglobulin administration, whereas three patients RA, a common systemic AD characterized by self-
exhibited minimal clinical symptoms. These gains were antibodies targeting citrullinated antigens, often results in
sustained across a 6 – 12-month follow-up period. Our persistent inflammation and synovial joint degeneration.
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previous study reported the first successful clinical trial of At present, the pathogenesis and etiology of RA remain
mRNA-based CAR-T cell therapy for Alzheimer’s disease, unclear. However, protein citrullination has long been
implying that CAR-T immunotherapy may become a new implicated as a primary trigger for the immune response
therapeutic option for Alzheimer’s disease. 57 in RA. 66,67 Notably, serum anti-citrullinated protein
MuSK MG is a life-threatening condition characterized antibodies detected in RA patients are strongly linked to
by severe muscular weakness. This weakness stems disease development and progression. Moreover, several
from the destruction of neuromuscular junction signal target proteins of anti-citrullinated protein antibodies have
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transmission caused by autoantibodies targeting MuSK. been identified.
Oh et al. designed a CAR for MuSK (MuSK-CAART) Zhang et al. utilized universal anti-fluorescein
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that includes the extracellular domain of MuSK and the isothiocyanate (FITC) CAR-T cells to target FITC-labeled
CD137-CD3ζ signaling domain, to precisely target B cells antigenic peptide epitopes and eliminate the autoreactive B
expressing autoantibodies against MuSK. The MuSK- cell subpopulation recognizing these antigens in RA to solve
CAART cells demonstrated therapeutic effects in terms of the challenges of selectivity and durability associated with
killing anti-MuSK B cells and preserving cellular cytotoxic RA therapy. Four guanine peptide epitopes derived from
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activity. The MuSK-CAART decreased anti-MuSK IgG guanine autoantigens were selected as ligands for targeting
without affecting total B cell count or total IgG levels in autoreactive B cells: guanine-modified vimentin, guanine-
EAMG, indicating the depletion of MuSK-specific B modified Type II collagen, guanine fibronectin, myosin-C,
cells. A clinical trial is currently underway to explore the and cyclic guanine peptide-1. T cells expressing a fixed anti-
safety and dosing of MuSK-CAART cells in patients with FITC CAR were generated and utilized as universal CAR-T
MuSK-MG (NCT05451212) (Table 2). 35 cells to precisely eliminate protein-specific autoreactive B
cells by recognizing FITC-labeled autoantigenic peptide
3.5. Application of CAR-T cells in the treatment of epitopes. Their findings indicated that anti-FITC CAR-T
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neuromyelitis optica spectrum disease (NMOSD) cells can be precisely guided to destroy hybridoma cells
Neuromyelitis optica (NMO) was originally described created through peptide vaccination and autoreactive
as a form of MS characterized by both optic neuritis and B cell subsets from RA patients. This method provides a
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myelitis. Antibodies against aquaporin-4 (AQP 4) were precise treatment strategy for RA and may be applicable to
found in 2004, allowing NMO to be distinguished from other systemic ADs. 28
MS. 59-61 NMO can cause ocular neuritis or transverse The HLA-II-encoded MHCII molecules can transmit
myelitis, as well as a variety of clinical symptoms, including extracellular antigens to CD4+ T cells, initiating their
posterior brain, diencephalon, brainstem, and symptomatic activation and proliferation. Upon activation, CD4+
brain syndromes caused by AQP 4-IgG antibodies. Thus, T cells further stimulate B cells to produce antigen-
NMO was renamed NMOSD. 62 specific antibodies. Notably, the HLA-DR1 variant is
A clinical trial investigating CD19 and CD20 CAR-T associated with susceptibility to RA. Therefore, the
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cells (NCT03605238) for NMOSD was halted because targeted recognition of RA-associated HLA-DR CD4+ T
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of recruiting issues. However, a Phase I clinical study cells is a feasible method to treat RA. Whittington et al.
(NCT04561557) examining BCMA CAR-T cell therapy in developed HLA-DR1 CARs to precisely target CD4+ T

Volume 3 Issue 2 (2024) 7 doi: 10.36922/gpd.2851