Chimeric Antigen Receptor Strategies can be Used to Target and Destroy Specific Classes of Unwanted Immune Cell

The work noted here is targeted at curing autoimmune conditions by removing the misconfigured immune cells that attack important infrastructure in tissues. This is good news for all autoimmunity in which the relevant biochemistry is fairly well understood - where the target immune cells can be well described in terms of their distinctive surface chemistry. However this is also very good news for the prospects of rejuvenating the aged adaptive immune system, wherein much of the problem is that the available capacity for immune cells is used up by an excess of cells uselessly specific to persistent viruses such as cytomegalovirus. There are too many of those cells and too little space left over for cells capable of responding to new threats. Clearing out the majority of those unwanted cells would go a fair way towards removing the contribution of the failing immune system to increased vulnerability to pathogens, cancer risk, and presence of senescent cells in aging. All that is needed is a good technology platform on which to build such a targeted therapy, and the work here seems like a sizable step in the right direction.

Researchers have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients' T cells. In human trials, researchers remove some of patients' T cells then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells - so that they swiftly destroy their targets.

Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas have been successful in some patients for whom all standard therapies had failed. B cells, which produce antibodies, can also cause autoimmunity. Researchers took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. "We thought we could adapt this technology that's really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease. Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field."

In the new study the team took aim at pemphigus vulgaris. This condition occurs when a patient's antibodies attack desmoglein (Dsg1 and Dsg3) molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal. To treat PV without causing broad immunosuppression, the team designed an artificial CAR-type receptor that would direct patients' T cells to attack only the B cells producing harmful anti-Dsg3 antibodies. The team developed a "chimeric autoantibody receptor," or CAAR, that displays fragments of the autoantigen Dsg3 - the same fragments to which PV-causing antibodies and their B cells typically bind. The artificial receptor acts as a lure for the B cells that target Dsg3, bringing them into fatal contact with the therapeutic T cells. Testing many variants, the team eventually found an artificial receptor design that worked well in cell culture, enabling host T cells to efficiently destroy cells producing antibodies to desmoglein, including those derived from PV patients. The engineered T cells also performed successfully in a mouse model of PV, killing desmoglein-specific B cells and preventing blistering and other manifestations of autoimmunity in the animals. "We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works."



Why is it so hard to find the auto-antigen targets of auto-immune diseases? Surely you could just run some kind of screen of potential antigens against B cells in culture?

Posted by: Jim at July 1st, 2016 8:52 AM

@Jim: I'm not technical enough in this field to give a good answer to that question. I would suggest reading around the research on molecular biology in rheumatoid arthritis, as that's a great example of a condition in which no-one appears to know anything for certain: which cells are involved, how they are deciding to attack, why there seems to be little consistency in investigations, etc, etc.

Posted by: Reason at July 1st, 2016 1:38 PM

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