The Immunotherapy Revolution for Autoimmune Diseases

Wynne Parry - Autoimmune diseases are a conundrum: Sometimes instead of protecting the body, the immune system turns against it. The target of its wrath varies depending on the condition. To alleviate patients' suffering, doctors must dampen the immune system. However, lacking the means to selectively target only the parts that are misbehaving, they have no choice but to broadly impair the body’s defenses, opening the door to potentially life-threatening malignancies and infections. This tradeoff has long frustrated Aimee Payne, MD, PhD, a professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, who treats and studies pemphigus vulgaris, an autoimmune condition that causes the skin to blister and peel because immune proteins known as antibodies attack an adhesive molecule in skin, desmoglein 3. “Why are we wiping out all of the immune cells, including the good immune cells that are helping to protect someone?” she said. “We should just be able to identify the ones causing pemphigus or another autoimmune disease and eliminate them with laser focus.” New research, including that by her lab, is striving to make such precision treatments a reality for pemphigus and certain other conditions. These experimental efforts belong to a larger wave of advancements in immunotherapy driven by basic discoveries about the body’s defensive system and the development of new techniques for manipulating it.Just as Penn Medicine has established itself as an epicenter for the revolution in immunotherapy that has transformed cancer medicine, the institution has now set its sights on autoimmunity, a category that includes more than 80 disorders affecting more than 20 million people in the U.S. Working at the leading edge of the field, Payne and other Penn Medicine researchers aim to bring less-damaging, longer-lasting—perhaps even permanent—relief to patients by addressing the source of their disease. Two gifts from Stewart and Judy Colton totaling $60 million since 2021 have bolstered this effort, establishing Penn Medicine’s new Colton Center for Autoimmunity. The center supports researchers as they dive deeply into mechanisms underlying autoimmune diseases, and so identify the basis for new therapies. These immune-targeting approaches can directly address the misguided activity at the heart of autoimmune conditions, and more, according to E. John Wherry, PhD, director of Penn’s Colton Center and Institute for Immunology & Immune Health and chair of Systems Pharmacology and Translational Therapeutics. Immunotherapies also have the potential to harness the immune system’s inherent ability to remember past threats. By tapping into immunological memory, immune-based drugs could potentially have effects that endure long after patients have stopped taking them. “We're not talking about treating autoimmunity, we're talking about curing the disease and making a permanent change in the body,” Wherry said.A Discovery Suggests a Path for More Selective Therapies Devising new immune-targeting therapies requires a deep understanding of the intricacies of the immune system. In a study published in Science Immunology in April, a team led by immunology researcher Neil Romberg, MD identified a promising subtlety in the lineages of T cells. Within clusters of cells known as germinal centers, T cells help B cells produce antibodies tuned to latch onto targets on invading microbes or, in cases of autoimmunity, on the body’s own cells. A specific population of T cells, known as T follicular regulatory (Tfr) cells, oversees this process. “Historically, people have thought that a single type of Tfr cells maintains protective immune responses to microbes while also directing them away from self-injury,” said Romberg, an associate professor of Pediatrics in the Perelman School of Medicine and clinical immunologist at Children’s Hospital of Philadelphia (CHOP). Using tonsils collected from healthy patients, the researchers instead identified two types of Tfr cells that appear to split up these tasks. One descends out of cell lineages known to calm the immune response. The second line of Tfrs originates from a variety of T cells that promotes the production of antibodies. Unlike their counterparts, these more combative Tfrs sport a marker protein known as CD38. With this differentiation in mind, Romberg envisions devising ways to selectively manipulate these populations, with the goal of improving the immune system’s ability to tolerate whatever it has mistakenly labeled an enemy—without affecting its ability to protect the body in general. “What if we could be uncompromising in the way we apply these therapies,” he said, “so we don’t have to accept these tradeoffs?” Tweaking CAR T to Treat Autoimmunity The breakthrough that established Penn Medicine’s pre-eminence in cell-based immunotherapy, the development of CAR T, is now providing a basis for new approaches to certain autoimmune disorders.CAR T endows T cells with artificial receptors (chimeric antigen receptors, or CARs) so they can find and destroy cells the receptor is designed to bind to, such as B cells that run amok in leukemia and lymphoma. Because pemphigus also results from B cell activity, Payne’s lab has long looked to these blood cancers for inspiration. Roughly a decade ago, when the first early trials of CAR T had begun to show success, Christoph Ellebrecht, MD, then a research fellow in Payne’s lab and now an assistant professor of Dermatology, suggested adapting that method to treat pemphigus vulgaris and other autoimmune diseases. If CAR T could wipe out cancerous B cells, why not other problematic B cells? Payne recognized the potential. “My reaction was—that’s brilliant,” she said.Ellebrecht initially worked on his idea with Vijay Bhoj, MD, PhD, then a postdoc in Michael Milone’s lab and now an assistant professor of Pathology and Laboratory Medicine. Conventional CAR T seeks to eradicate all of a patient’s B cells; together with Payne and Milone, they sought to make their version more selective by topping the receptor with the skin protein desmoglein 3, the target of the antibodies in pemphigus. “The idea is that the receptor will only bind to the bad antibody-expressing B cells and specifically kill those, not the B cells that protect against tetanus infections, COVID-19, measles, and whatnot,” Bhoj said.A spinoff company co-founded by Payne and Milone, Cabaletta Bio, has clinical trials underway testing therapies based on this strategy, dubbed CAAR T for chimeric autoantibody receptor, for specific subtypes of pemphigus and myasthenia gravis, a neuromuscular condition. Meanwhile, other applications are in the works. Bhoj recognized CAAR T’s potential to remedy a blood condition he treats. In the autoimmune form of thrombotic thrombocytopenic purpura (TTP), antibodies attack an enzyme, ADAMTS13, that prevents the formation of blood clots. When this enzyme is depleted, clotting interferes with blood flow in small vessels throughout the body. His group is now testing an experimental CAAR T treatment for this condition in animal models. While the straightforward, well-defined dynamics underlying pemphigus vulgaris, TTP, and certain other autoimmune diseases lend themselves to CAAR T, the causes of many others do not. In some of these cases, however, preliminary research suggests a conventional CAR T approach has promise. In one recent study based in Germany, five patients with lupus, a disorder in which antibodies attack DNA, went into remission after their T cells were engineered to wipe out their B cells.These cell-based immunotherapies are still in experimental stages for patients, with plenty more potential therapies still under investigation that are not yet ready for clinical testing. But researchers hold out hope that they could eventually have impacts on autoimmune diseases as real as those for cancer.Bhoj thinks of a patient he saw recently. Although he has received conventional B cell depleting therapy, the man came into the hospital in late May with his fourth relapse. In contrast, evidence from CAR T suggests these engineered cells can more effectively infiltrate the body to find their targets and persist for long periods, perhaps indefinitely, within it. “I'm working on it because I think there is a potential that these approaches could be curative,” Bhoj said. “There are no guarantees, but it’s good to aim high.” - Source: pennmedicine.orgDid you know?AntibodiesSoldiersSometimes dubbed “the soldiers of immunity,” T cells are among the most ruthless warriors in the immune system’s arsenal.STATS: T cellsT cells are part of the immune system Develop from stem cells in the bone marrowThey help protect the body from infection May help fight cancer.

The Immunotherapy Revolution for Autoimmune Diseases

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Allgemeine Zeitung 2024-11-26

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The Immunotherapy Revolution for Autoimmune Diseases

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Allgemeine Zeitung 2024-11-26

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