Autoimmune disease refers to the disease in which the immune system reacts to the host's
own body and causes damage to tissues and organs. At present, the pathogenesis of various
autoimmune diseases is still not well understood, but an imbalanced immune tolerance
plays a key role in this process.
An ideal therapy to autoimmune disease should eradicate pathogenic autoimmune cells but
retain the protective immunity. The chimeric antigen receptor-modified T (CAR-T) cell
technology has proven to be highly effective in targeting B cell malignancies, and the
treatment-induced B cell and antibody deficiencies have implications for treating
autoantibody-related autoimmune diseases. Studies have shown that CAR-T cells targeting B
cell surface molecules can kill autoreactive B lymphocytes in pemphigus vulgaris (PV) and
systemic lupus erythematosus (SLE) patients. Thus, CAR-T targeting antibody-producing
cells has potential in treating autoimmune diseases including PV, SLE, autoimmune
hemolytic anemia, Sjogren's syndrome etc..
MSCs have immune modulatory and immunosuppressive effects. MSCs have been extensively
studied and clinically evaluated for the treatment of autoimmune diseases and graft
versus host disease (GVHD) caused by hematopoietic stem cell transplantation (HSCT). In
many studies, MSCs have demonstrated promising beneficial effects that can reduce severe
autoimmune reactions. In recent years, MSCs have been used in synergy with CAR-T cells to
address the shortcomings of CAR-T cells. Fetal tissue-derived clonal MSCs (fMSCs) have
extended expansion potential and express rich levels of various growth factors. The fMSCs
also resove a main limitation in MSC quality and reliability issues related to product
consistency of MSCs. As such, innovative strategies to maximise the synergistic effects
of CAR-Ts and MSCs have been proposed by either using MSCs as a supplementary
intervention to assist in CAR-T based immunotherapies or as part of a sequential therapy
regimen.
CD19- and BCMA-specific CAR is based on activation of intracellular signalijng domains of
T cells by the extracellular single chain variable fragment (scFv) antibodies against
CD19 and BCMA. The activated CAR-T cells can target and kill B cells. The investigation
plans to use genetically modified T cells to express 4th generation lentiviral CARs with
an inducible caspase 9 self-withdrawal gene (4SCAR) to increase the safety of this
specific approach. Besides targeting CD19 and BCMA, other B cell and plasma cell surface
molecules will also be targeted and included in the treatment design. Based on
accumulated experiences, the 4SCAR T cells have shown high safety profile without serious
cytokine release syndrome (CRS) or neural toxicities in patients. Through this trial, the
safety and long-term efficacy of synergistic B-cell- and plasma-cell-specific 4SCAR
T-cell therapy with MSCs will be evaluated, providing clinical evidence to support the
use of 4SCAR-T cells and MSCs in the treatment of autoimmune diseases.