CRISPR-Modified Cells Offer Remission for Autoimmune Patients

Three patients are in “safe, deep remission” after receiving a CRISPR-Cas9-modified cell therapy for autoimmune disease treatment, according to a new published study in Cell.

The results are from an ongoing clinical trial (NCT05859997) led by Dr. Xu Huji, professor of medicine in Tsinghua University and Second Military Medical University (SMMU) in Shanghai, and sponsored by Bioray Laboratories.

Donor cells could expand opportunities for CAR T-cell therapy

Unlike traditional chimeric antigen receptor (CAR) T-cell therapy, the novel treatment – called BRL-301 – uses donated T cells, an approach known as allogeneic or universal cell therapy.

While several CAR T-cell therapies are approved to treat conditions such as cancer, their reliance on autologous cells – cells derived from the patient – is a major bottleneck.

Autologous CAR T-cell therapy is a form of targeted therapy. Typically, their manufacturing involves extracting a patient’s T cells, transporting them to a laboratory and genetically engineering the cells to present CARs on their surface. The CAR binds to a specific receptor on the surface of a target cell in the body – such as cancer cells. The modified CAR T cells are then returned to the patient via intravenous administration.

Though the personalized element underpins the success of CAR T-cell therapy, it’s a labor intensive and costly process, limiting scale-up opportunities and accessibility for patients. The prospect of using donor cells to create off-the-shelf, universal CAR T cells is therefore highly appealing to manufacturers, physicians and patients alike.

The core challenge here, however, is ensuring that the patient’s immune system does not attack the donor cells, or that the grafted cells do not attack the patient’s body.

Huji and colleagues utilized CRISPR gene-editing technology to overcome this issue when developing BRL-301. They obtained T cells from a 21-year-old female and knocked out 5 genes known to be involved in immune rejection.

“T cells isolated from PBMCs [peripheral blood mononuclear cells] were first transduced with lentivirus coding anti-CD19 CAR construct and then were knocked out for human leukocyte antigen (HLA)-A, HLA-B, class II major histocompatibility complex transactivator (CIITA), T cell receptor alpha constant (TRAC) and PD-1 by electroporation-based CRISPR-Cas9 gene editing using Cas9 protein in complex with single guide RNAs (sgRNAs) for each target,” they explained. “Afterward, the T cells were expanded in vitro for 12 days.”

The donor’s T cells were embellished with CARs that recognize and bind to CD19, a receptor found on the surface of B cells. “Autologous CAR T-cell therapy has been hailed as one of the greatest breakthroughs in the treatment of B-cell malignancies, including refractory relapse leukemia and lymphomas,” Huji and colleagues described. “Similar to B-cell malignancies, autoantibody-related autoimmune diseases are rooted in developmental and functional abnormalities of the B cell compartment.”

The therapy was then tested in three patients: a woman diagnosed with an immune condition that causes muscle weakness and does not respond to conventional treatment, and two males diagnosed with diffuse cutaneous systemic sclerosis.

Promising immune modulatory effects of off-the-shelf CAR T cells

Huji and colleagues found that the CRISPR-modified cells were detectable for over three months. The treated patients achieved complete B-cell depletion, including B cells implicated in the pathophysiology of their autoimmune disorders.

“During the six-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis,” the researchers said.

Cytokine release syndrome is an adverse reaction that can occur in CAR T-cell therapy. While it’s encouraging that the patients in this case study didn’t experience such a reaction, further studies will be required to establish the treatments long-term effects, and its efficacy in wider cohorts.   

"Although all three patients relieved quickly after receiving the treatment and continued to respond even after the recovery of lymphocytes including B cells, we will continue monitoring all patients beyond the reported six-month period for the long-term efficacy and safety profile,” Huji and team said.

One dose of the CAR T-cell therapy was administered in this study. As it was well-tolerated, the researchers also suggest that future trials could assess the effectiveness of higher or multiple doses.

“Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR T cells in treating severe refractory autoimmune diseases,” the research team concluded.

Reference: Wang X, Wu X, Tan B, et al. Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis. Cell. 2024;187(18):4890-4904.e9. doi: 10.1016/j.cell.2024.06.027