Autoimmune Diseases Therapy: Targeted by Chimeric Antigen Receptor T cells

This article is reproduced from Science Magazine (Science 01 Jul 2016: Vol. 353, Issue 6294, pp. 14 DOI: 10.1126/science.353.6294.14) Fighting autoimmunity with immune cells. In this article, the possibility of the solving some autoimmune diseases with immune cells is discussed.

Autoimmune diseases share a grim similarity with cancer: People’s own cells become their enemies. But a new study published online in Science reveals a happier parallel, suggesting that a therapy designed to harness the immune system to attack cancer cells may also cull the turncoat immune cells behind certain autoimmune diseases.

The approach relies on chimeric antigen receptor T cells, or CAR T cells: immune cells genetically modified to home in on a desired target on cancer cells or—in this case—on rogue B cells, another immune cell type. The new study only gauged the CAR T cells’ capabilities in the lab dish and in mice, but some scientists are already using the B word: breakthrough. Removing only the self-destructive cells has been the Holy Grail for treating autoimmune diseases, “but it hasn’t been solved for any autoimmune disease up to now,” says dermatologist Rüdiger Eming of the Philipp University of Marburg in Germany. “Using this approach you are able to specifically target the pathogenic immune cells without major side effects.”

The basic recipe for producing CAR T cells dates to the late 1980s. Scientists remove some of a cancer patient’s T cells and genetically tweak them so that receptors on their surface can detect a specific molecule, or antigen, on cancer cells. After the modified T cells are returned to the patient’s bloodstream, they hunt down and destroy cancer cells carrying that antigen.

Fig. 1 T cells like this one (yellow) attacking a cancer cell can be altered to fight autoimmunity.

In some early clinical trials, CAR T cells showed dramatic results against blood cancers such as acute lymphoblastic leukemia, banishing all signs of disease from more than 90% of patients (Science, 20 December 2013, p. 1432). Now, researchers are starting to test them against solid tumors, with dozens of trials underway for cancers from glioblastoma to lymphoma.

A few scientists are also investigating whether CAR T cells could rein in our immune system. In some people with hemophilia, for example, the cells might be able to prevent the normal immune response from destroying recombinant factor VIII, a clot-promoting protein used to treat the condition. The new work goes further by suggesting that CAR T cells could be protective in an autoimmune disease.

For the study, dermatologist Aimee Payne and cancer immunotherapist Michael Milone of the University of Pennsylvania and their colleagues took aim at the autoimmune disease pemphigus vulgaris. In this illness, B cells pour out antibodies that attack desmoglein 3, a protein that helps lock together cells in the skin and mucous membranes. Sufferers develop painful blisters—on the skin; in the mouth or esophagus, where they can hinder eating and swallowing; and even in the eyes, nose, and genitals. Untreated, the disease can kill.

The steroid prednisone and immune-suppressing drugs can improve quality of life, but they can cripple the immune system’s ability to fight off pathogens, sometimes leading to fatal infections. A more specific drug, the monoclonal antibody rituximab, kills only B cells but can still dangerously undermine immune function.

To determine whether CAR T cells could do better, Payne, Milone, and colleagues engineered human T cells to recognize just those B cells that produce antibodies against desmoglein 3. They then showed that the engineered cells could kill cancerous B cells that pump out the same antibodies—first in a lab dish, then in mice injected with the B cells to mimic the human disease. The CAR T cells slashed the amount of anti-desmoglein 3 antibodies in the animals’ blood and prevented them from developing mouth blisters.

One worry is that CAR T cells could go astray, for example by attacking incorrect targets in the skin. But the researchers saw no signs of such misdirected attacks in mice given human CAR T cells and human skin grafts. The scientists did see encouraging hints that some CAR T cells settled down in the mice and thus might keep symptoms from returning. “We show that these cells specifically kill the disease-specific B cells and have potential for long-term disease control,” Payne says.

“This is a very unique, novel, and creative approach,” says molecular immunologist A. Razzaque Ahmed of Tufts University School of Medicine in Boston. But hematologist Zachary Spigelman, also of Tufts, cautions that the mouse experiments didn’t demonstrate that CAR T cells can reverse the disease, only that they can prevent symptoms from developing. “It’s an excellent first step, but it’s not a proof of concept.”

Pemphigus vulgaris is rare, with fewer than 100,000 cases in the United States, but Payne and Milone think CAR T cells could be unleashed on other autoimmune diseases in which self-targeted antibodies attack a single main antigen. One is myasthenia gravis, which can cause severe weakness and even death as antibodies destroy the molecule that allows nerves to stimulate muscles.

CAR T cells may not work for more common and complex autoimmune diseases, such as multiple sclerosis or type 1 diabetes, and they have triggered serious side effects in some cancer patients. Because autoimmune diseases are not usually fatal immediately, “the bar [for safety] is higher than in the cancer setting,” Milone says.

So he and his colleagues are moving cautiously. Next, “we want to cure dogs with pemphigus,” Payne says. Dogs are one of the few species besides humans that naturally develop the disease. Besides benefitting the animals, she says, demonstrating that CAR T cells can alleviate pemphigus vulgaris in dogs “would break down barriers for potential future human trials.”