Engineered T Cells Police the Immune System, Eliminate Its Bad Apples

This is a schematic of how a chimeric autoantibody receptor, or CAAR, that displays fragments of the autoantigen Dsg3 helps fight an autoimmune disease called pemphigus vulgaris, a condition in which a patient’s own immune cells attack Dsg3, which normally adheres skin cells. [Christoph T. Ellebrecht, M.D./Perelman School of Medicine, University of Pennsylvania]

Who will police the police? The age-old question keeps recurring in new contexts, including autoimmunity, an aberrant state in which normally protective cells become overzealous. To date, it has not been possible to suppress rogue immune cells without dampening the immune system generally. But a more targeted approach is being developed. It involves the engineering of T cells that can eliminate rogue cells while sparing healthy immune cells that still protect the body.

This new approach borrows from a promising anticancer strategy by which T cells are engineered to destroy malignant cells. T cells can be equipped with artificial target-recognizing receptors, called chimeric antigen receptors, or CARs. Experimental CAR T-cell treatments have shown promise against B cell leukemias and lymphomas, cancers in which patients' healthy B cells turn cancerous.

If T cells can be turned against B cells that cause cancer, why not try turning them against B cells that cause autoimmune disease? This question occurred to scientists based at the University of Pennsylvania School of Medicine. These scientists decided to crack down on B cells that cause pemphigus vulgaris (PV), a life-threating autoimmune disease that results in blistered skin.

The scientists reported their work June 30 in the journal Science, in an article entitled, “Reengineering Chimeric Antigen Receptor T Cells for Targeted Therapy of Autoimmune Disease.” The article described how autoantigen-based chimeric immunoreceptors were used to direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor.

“We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains,” wrote the article’s authors. “Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo.”

The scientists demonstrated their new technique by successfully treating an otherwise fatal autoimmune disease in a mouse model, without apparent off-target effects, which could harm healthy tissue. “This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said Aimee S. Payne, M.D., Ph.D., an associate professor of dermatology at Penn and the Science article’s co-senior author.

T-cell therapies can be complicated by many factors. But in these experiments, the Penn scientists' engineered cells maintained their potency despite the presence of anti-Dsg3 antibodies that might have swarmed their artificial receptors. In addition, there were no signs that the engineered T cells caused side effects by hitting the wrong cellular targets in the mice.

The Penn team now plans to test their treatment in dogs, which can also develop PV and often die from the disease. “If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in human pemphigus patients,” noted Dr. Payne.

Also on the horizon for the Penn scientists are applications of CAAR T-cell technology for other types of autoimmunity. The immune rejection that complicates organ transplants, and normally requires long-term immunosuppressive drug therapy, may also be treatable with CAAR T-cell technology.

“If you can identify a specific marker of a B cell that you want to target, then in principle this strategy can work,” Dr. Payne concluded.