Engineering the Immune System to Correct its Own Flaws: a Q&A with Dr. Aimee Payne

In a study with potentially major implications for the future treatment of autoimmunity and related conditions, scientists from the Perelman School of Medicine at the University of Pennsylvania 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 autoimmune disease the team studied is called pemphigus vulgaris (PV), a condition in which a patient’s own immune cells attack a protein called desmoglein-3 (Dsg3) that normally adheres skin cells.

This exciting aspect is why CAR-T cells were named by the director of the NIH and Vice President Joe Biden as part of the “moonshot” to cure cancer – the word “cure” is potentially within our reach with this technology. Current therapies for autoimmune disease, such as prednisone and rituximab, suppress large parts of the immune system, leaving patients vulnerable to potentially fatal opportunistic infections and cancers.

The Penn researchers 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. The results are published in an online First Release paper in Science. “This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect from infection,” said the study’s co-senior author Aimee S. Payne, MD, PhD, the Albert M. Kligman Associate Professor of Dermatology. Payne and her co-senior author Michael C. Milone, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, adapted the technique from the promising anti-cancer strategy by which T cells are engineered to destroy malignant cells in certain leukemias and lymphomas. “Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.

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 through a process similar to dialysis and 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. The basic CAR T cell concept was first described in the late 1980s, principally as an anti-cancer strategy, but technical challenges delayed its translation into successful therapies.

Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas — cancers in which patients’ healthy B cells turn cancerous — have been successful in some patients for whom all standard therapies had failed. B cells, which produce antibodies, can also cause autoimmunity. Payne researches autoimmunity, and a few years ago, a postdoctoral researcher in her laboratory, Christoph T. Ellebrecht, MD, took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. Soon Payne’s lab teamed up with Milone’s, which studies CAR T cell technology, in the hope of finding a powerful new way to treat these ailments.

“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,” said Milone. “Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field,” noted Payne. A more disease-specific receptor In the new study, for which Ellebrecht was first author, the team took aim at pemphigus vulgaris. This clinically serious condition occurs when a patient’s antibodies attack molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal, but in recent decades the condition has been treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil, and rituximab.

To treat PV without causing broad immunosuppression, the Penn 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, as Payne’s laboratory and others have shown in prior studies. 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,” Payne said. 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 team now plans to test their treatment in dogs, which also can 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,” Payne said. 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,” Payne said. In addition to Payne, Milone and Ellebrecht, co-authors of the study include Vijay G. Bhoj, Arben Nace, Eun Jung Choi, Xuming Mao, Michael Jeffrey Cho, John T. Seykora and George Cotsarelis, all of Penn; Giovanni Di Zenzo of the Istituto Dermopatico dell’Immacolata in Rome; and Antonio Lanzavecchia of the Institute for Research in Biomedicine in Bellinzona, Switzerland.

Researchers have engineered T cells to target and kill a malfunctioning component of the immune system responsible for autoimmune disease, while sparing healthy immune cells that still protect the body. The work brings scientists closer to targeting only the disease-causing cells in autoimmune diseases, which isn’t possible now. Some autoimmune diseases occur when a subset of B cells, which respond to specific signatures of pathogens, incorrectly see a person’s own tissue as foreign, prompting the rest of the immune system to attack. Currently, strategies to treat autoimmune diseases involve wide-sweeping immunosuppression, which can leave a patient more susceptible to infection; what’s more, patients often experience relapse following such treatments. Now, initial results in mice by Christoph Ellebrecht et al. show that a more targeted approach may be viable for treating autoimmune disease. Inspired by a technique that has recently shown success for treating leukemia, the researchers explored how chimeric antigen receptors (CARs) may be used to target rogue B cells. CAR techniques involve harvesting the antibodies that trigger an immune response and fusing them to pathogen-killing T cells. By tweaking this technique, researchers can create an arsenal of T cells that target a specific pathogen – or in the case of autoimmune diseases, the abnormal B cells. Pemphigus vulgaris (PV) is a life-threatening autoimmune disease that results in blistered skin. Here, the team harvested the key protein, Dsg3, that disease-causing B cells recognize, and fused it to signaling proteins that activate T cells. When the researchers infused mice with the engineered T cells, their levels of Dsg3-targeting B cells decreased, as did the occurrence of blisters. Furthermore, these engineered T cells can divide and proliferate, the researchers show, suggesting that CAR techniques to treat PV, and perhaps other autoimmune diseases, could have long-lasting effects.

What does this mean for our community?

Noelle DeLaney, the IPPF’s Patient Support Manager, asked Dr. Payne!

Noelle DeLaney (ND): Can you speculate about how this treatment might be translated to clinical practice?

Dr. Aimee Payne (AP): CAR-T cells have already been used in humans to treat cancer. At this point in time, we have generated just about the same amount of preclinical data as our cancer colleagues showed prior to starting clinical trials in humans, but pemphigus is not as quickly fatal as the cancers were in the initial patients they treated. Thus, we want to set a “higher bar” of evidence that these CAAR-T cells will work in pemphigus. So, we are taking a two-pronged approach: we are initiating discussions on how we would design and gain approval for a first-in-human trial for CAAR-T cells, and at the same time we are seeking to open clinical trials for dogs with pemphigus. Dogs are one of the only animals other than humans that spontaneously develop pemphigus. If we can show that we can safely treat and potential cure dogs with pemphigus, we think that will convince both doctors and patients to begin enrolling for human clinical trials of CAAR-T therapy.

ND: Is there a role for Pharma? If not, how will clinical trials be funded?

AP: Yes. The right partnerships will be essential. Pharmaceutical companies, universities, the NIH, and philanthropic donors have funded the CAR-T cell work in cancer. We need to make sure we have adequate resources to support the lab-based scientists, the clinical treatment teams, and the overall research infrastructure to safely and effectively move forward this technology to human clinical trials.

ND: How is it that this could qualify as an actual cure?

AP: The unique feature of CAAR-T cells is that they are a “living therapy.” Unlike an antibody-based therapy, in which a defined dose is infused, CAAR-T cells can expand over 1000-fold in vivo when they see their target (they can spawn new soldiers to fight off the enemy, if you will.) Additionally, we know from prior studies that they can also make memory T cells that can persist for decades. So you only infuse the CAAR-T cells once, and they will kill all pemphigus B cells, then go dormant. If a pemphigus B cell should recur at any point in the future, the memory CAAR-T cells can expand again and kill them.  This exciting aspect is why CAR-T cells were named by the director of the NIH and Vice President Joe Biden as part of the “moonshot” to cure cancer – the word “cure” is potentially within our reach with this technology.

 ND: Do you have any information for patients wanting to participate in future trials?

AP: Stay tuned! We are still some amount of time away from human trials.

ND: Are there implications for other diseases or types of diseases/disorders this treatment could be used for (autoimmune and other)?

AP: Yes – this therapy could theoretically be used for any antibody-mediated disease, including other autoimmune blistering diseases like bullous pemphigoid epidermolysis bullosa acquisita, and even non-skin autoimmune diseases such as myasthenia gravis and many others.

ND: What do you want pemphigus and pemphigoid patients to take away from this?

AP: We are optimistic that research will lead to better therapies and options for pemphigus and pemphigoid patients, but it’s by no means easy! Research support from the NIH and other sources has been dwindling over the last several years, and due to the rarity of pemphigus and pemphigoid, it has become increasingly difficult to advocate for research into mechanisms of disease and potential treatments for these diseases. Our community is in danger of losing outstanding research programs, and once that infrastructure is gone, there won’t be the intellectual capital remaining to make sure that future generations of doctors and researchers continue to focus on these devastating diseases. Please keep up all the great work you are doing at the IPPF in regard to advocacy and meetings to bring together doctors, researchers, and patients to talk about their disease and what the future may hold.

Dr. Aimee Payne is the Albert M. Kligman Associate Professor of Dermatology at the University of Pennsylvania. Her career interest has been in pemphigus: diagnosing and treating patients with this potentially fatal autoimmune disease, and performing research to better understand disease, with the goal of improving therapy. Dr. Payne received her BS in Biology from Stanford University and her MD/PhD from Washington University School of Medicine, followed by residency and postdoctoral fellowship training in Dermatology at the University of Pennsylvania. Her laboratory has cloned B cell repertoires from pemphigus patients to better understand why disease occurs, which has discovered common features of the immune response among patients. Her laboratory has also focused on patient-oriented research to improve pemphigus therapy, which has led to a better understanding of how rituximab works in pemphigus, as well as the development of novel targeted therapies. Dr. Payne’s work in the field has been recognized with the American Academy of Dermatology Young Investigator Award, the Charles and Daneen Stiefel Award in Autoimmune Diseases, the Sanofi Innovation Award, and election to the American Society for Clinical Investigation. Dr. Payne is also active in mentoring the next generation of physician-scientists through teaching medical students, graduate students, and dermatology residents. She serves as Associate Director of the Medical Scientist Training Program at Penn and faculty advisor for the Association of Women Student MD-PhDs (AWSM).

Come see Dr. Payne discuss this exciting research at our annual patient conference in Austin!