CAR T-cell Therapy Has Potential to Combat Lupus, Mouse Study Shows
Eliminating B-cells using a recent form of immunotherapy that employs genetically modified T-cells is able to treat lupus in mice in a stable and efficient way, a study funded by Lupus Research Alliance shows.
The modified cells, called chimeric antigen receptor (CAR) T-cells, were able to significantly reverse disease symptoms and extend survival over one year in mouse models of lupus.
The discovery offers hope for employing this method of depleting B-cells as a new therapeutic option for lupus, opening the door for clinical studies to test this approach.
The report, “Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus,” was published in the journal Science Translational Medicine.
B-cells, white blood cells central for the functioning of the immune system, play an important role in lupus, including the production of autoantibodies, which trigger a harmful immune response against the body’s own tissues and organs.
B-cells also can activate other cells of the immune system and release a type of messenger molecules called cytokines, which further exacerbate inflammation and organ damage, contributing to disease flares.
Given its central role in lupus, depleting the number of B-cells has been attempted to treat the disease.
This strategy has been clinically tested through the use of rituximab (brand names Rituxan and Truxima), an anti-CD20 antibody that targets B-cells and is approved for some blood cancers and autoimmune conditions including rheumatoid arthritis.
The medicine has been evaluated in clinical trials for systemic lupus erythematosus (SLE) and lupus nephritis, but failed to result in significant clinical benefits, attributed to a temporary and incomplete B-cell elimination.
But now, professor Marko Radic, PhD, of the University of Tennessee Health Science Center and his colleagues devised a new approach to attain the efficient depletion of B-cells in lupus.
They figured that a novel technique, called CAR T-cells, which employs genetically modified T-cells to destroy target cells, would be a promising strategy.
This approach has been extensively tested and recently approved as a treatment for cancer, particularly B-cell cancers, but its potential beyond cancer therapy is gaining attention.
The team created genetically modified T-cells, immune cells key for orchestrating an immune response to invaders. Those cells were genetically engineered to express receptors on their surface, called chimeric antigen receptors (CARs) that allow T-cells to recognize and bind to CD19, a protein found at the surface of most B-cells.
The goal was to create T-cells able to specifically target and destroy B-cells.
When two different mouse lines, which exhibit lupus-like disease, were treated with an infusion anti-CD19 CAR T-cells, disease symptoms were significantly reduced and progression was delayed, while it reduced sharply the production of autoantibodies and the numbers of CD19 positive B-cells in the blood.
Also, CAR T-cells significantly prolonged the lifespan of mice compared with conventional care.
In addition, the CAR T-cell treatment eased several lupus manifestations including high protein levels in the urine, skin inflammation, and blood markers of chronic inflammation and autoimmunity.
An important observation was that after one year the CAR T-cells remained active and able to eliminate B-cells in mice.
“Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus,” the researchers stated in their report.
“These are exciting results,” Kenneth M. Farber, president and CEO of Lupus Research Alliance, said in a press release.
“When we awarded Dr. Radic the Novel Research Grant in 2014, using CAR T cells was just showing promise in cancer, and our scientific advisors recognized the potential of this extremely innovative approach for lupus. It has proven transformative for cancer patients, and we hope clinical research can demonstrate safety and effectiveness of CAR T cells in improving the lives of people with lupus,” Farber said.