Immunotherapy & The Autoimmune

Immunotherapy & The Autoimmune

“Every day my clothes and bedding were covered in blood. Every day I had to rub stain remover on these blood marks.” This is the story of Hilda.1 She suffers from a rare condition called autoimmune blistering disease, a heterogeneous group of disorders in which the immune system mistakenly attacks the healthy skin and mucosal tissue, causing painful blisters and lesions.2 The disease affects 1 in 250,000 people and occurs predominantly in individuals between the ages of 50-60. The disease is progressive, with blisters gradually spreading to cover a significant portion of the skin. Autoimmune blistering disease is a life-threatening condition if untreated, due to the risk of lesions spreading to the esophagus and blocking the patient’s airway. Currently, there is no cure for autoimmune blistering disease and treatment options only alleviates the symptoms of the condition.2 However, researchers at the University of Pennsylvania, have recently published a ground-breaking study in which autoimmune blistering disease was cured in mouse models by utilizing a new form of cancer treatment called immunotherapy.3 The researchers modified a potent white blood cell known as T-lymphocytes which are capable of killing unhealthy cells, to specifically target the pathogenic B cells erroneously harming the skin of these patients.3 These findings suggest an exciting possibility of cancer therapeutics being used to treat rare autoimmune diseases in the future.

The immune system is composed of a complex network of interdependent cells, substances, and organs that work together to protect the body from bacterial and viral infections, as well as playing a crucial role in preventing the uncontrolled growth of cells, or cancer.4 In other words, the immune system is a regulatory unit of the body that is constantly working to ensure that the host is protected from both external (e.g. bacteria) and internal dangers (e.g. cancer). This natural defense system, however, is imperfect and is known to get weaker and make mistakes over time.5 Autoimmune conditions are an example of this, where the immune system incorrectly identifies healthy cells as foreign and attacks specific organs and tissues.6 There are over 20 recognized autoimmune diseases, with many of them sharing similar symptoms.6 Patients suffering from autoimmune conditions are often misdiagnosed and only receive proper treatment following the consultation of multiple health professionals during advanced stages of the disease.6 In the body of healthy individuals, the immune system has a built in “screening” mechanism where T and B cells that are reactive to the host tissue cells are eliminated through a process known as central tolerance. In patients with autoimmune disorder, however, this mechanism breaks down, and the harmful T or B cells can survive and attack the host’s own tissues. In the case of Autoimmune blistering disease, autoreactive B cells develop antibodies antibodies that destroy a protein involved in skin adhesion called desmosomes, causing blisters to form on the skin.


“These findings suggest an exciting possibility of cancer therapeutics being used to treat rare autoimmune diseases in the future. “

The skin represents the largest organ of the body and consists of multiple layers of tissue. The outermost layer protects the skin and is referred to as the epidermis.2 Underlying the epidermis is the dermis layer, comprised of various specialized cells such as hair follicles. Blisters form when the epidermis separates from the dermis layer, creating a space that fills with fluid. Typically, this occurs because of damage to the skin. However, in patients with autoimmune disease, a protein molecule secreted by the immune system called antibodies, attacks desmosome adhesion proteins holding the layers of skin together. Antibodies are produced by an immune cell called B–lymphocytes, which identify and terminate specific foreign molecules. Normally, B cells produce antibodies that target virally or bacterially infected cells. In patients with autoimmune blistering disease, however, antibodies target proteins that adhere the layers of skin together, causing blisters to form.2

Current treatment methods involve the administration of corticosteroids, a group of immunosuppressive drugs that can alleviate blisters formed due to autoimmune blistering disease.2 However, the efficacy of treatment varies considerably among individuals and long-term administration of corticosteroids have serious side effects, ranging from thinning of bone to increased risk of diabetes. Also, corticosteroid non-specifically suppresses a significant portion of the immune system, leaving the patient vulnerable to many opportunistic pathogens.2


“Patients suffering from autoimmune conditions are often misdiagnosed and only receive proper treatment following the consultation of multiple health professionals during advanced stages of the disease.”

The publication by the researchers at the University of Pennsylvania adopted the principles of anti-cancer immunotherapy and applied it to the field of autoimmune disease treatment.3 Immunotherapy is an emerging field in cancer treatment and is designed to harness the body’s natural defenses against cancer.7 T-cell treatment is a type of immunotherapy in which the patient’s T cells are removed and changed in the laboratory to have specific detection proteins called receptors.8 These engineered receptors give the modified T cells the ability to recognize a protein that is only expressed by cancer cells. The re-engineering of natural immune cells within the patient’s body to combat cancer is referred to as chimeric antigen receptor (CAR) T-cell therapy. In the context of autoimmune disease treatment, the researcher took the principles of CAR therapy to design T cells that specifically kill only the B cells that are responsible for the formation of blisters. The application of CAR therapy to autoimmune diseases is referred to as chimeric autoantigen receptor (CAAR) therapy. Researchers completely cured autoimmune blistering disease in mouse models with no apparent off-target harm to healthy tissue. “This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” states Dr. Payne, one of the leading investigators in the publication.8 Personalized CAAR therapy would allow patients to be completely free of autoimmune disease-causing B cells with no repercussions to the integrity of their immune system.

Unfortunately, preclinical studies involving animals do not always translate successfully to humans because mouse models fail to mimic the extreme complexity of human physiology and disease progression.9 Therefore, the safety and efficacy of CAAR treatment reported by the researchers at the University of Pennsylvania may not translate to human trials. For example, in cancer therapeutic research, 85% of drugs fail early clinical trials even though they have strong animal model data. Autoimmune blistering disease expert Dr. Amagai states in an interview with the New England Journal of Medicine that it would be premature to proceed to human clinical trials based on the current findings reported on CAAR therapy.10 There needs to be more concrete evidence of re-engineered T cells being able to eliminate autoimmune B cells at all stages of disease progression.

Nevertheless, CAAR therapy is a novel approach to the development of autoimmune blistering disease treatment and may eventually develop into a therapeutic for humans. CAR T cell therapy is currently in the clinical trials phase of cancer immunotherapy and has demonstrated promising results against leukemia.7 The expansion of CAR therapy to autoimmune blistering disease will offer a more personalized therapeutic option for patients with fewer side effects compared to the current model of treatment involving corticosteroids. The successful translation of CAAR therapy to treat blistering disease will pave the way for other B – cell mediated autoimmune diseases in the future. Complete cures of autoimmune diseases through immunotherapy may be on the horizon.


Works Cited:

1. Helda. Helda. http://pemphigus.nl/pemphigus-en-pemfigoid/mijn-verhaal/truus/. Published 2006.
2. Peter Marinkovich M. Auto Immune Blistering Disease. NORD. https://rarediseases.org/rare-diseases/autoimmune-blistering-diseases/. Published 2015.
3. Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179-184. doi:10.1126/science.aaf6756.
4. Chaplin DD. 1. Overview of the human immune response. J Allergy Clin Immunol. 2006;117(2 Suppl Mini-Primer):S430-5. doi:10.1016/j.jaci.2005.09.034.
5. Smith DA, Germolec DR. Introduction to immunology and autoimmunity. Environ Health Perspect. 1999;107(Suppl 5):661-665. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1566249/.
6. Roddick J. Autoimmune Disease. Health Line. http://www.healthline.com/health/autoimmune-disorders#Overview1. Published 2015.
7. Snook AE, Waldman SA. Advances in cancer immunotherapy. Discov Med. 2013;15(81):120-125.
8. Kreeger K. New Therapy Treats Autoimmune Disease Without Harming Normal Immunity. PennMedicine.
9. Mak IWY, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014;6(2):114-118. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902221/.
10. Amagai M. Modulating Immunity to Treat Autoimmune Disease. N Engl J Med. 2016;375(15):1487-1489. doi:10.1056/NEJMcibr1608900.


Cite This Article:

Chon J., Zheng K., Chan G., Ho J. Immunotherapy & The Autoimmune. Illustrated by C. Nguyen. Rare Disease Review. February 2017. DOI:10.13140/RG.2.2.13888.12807.

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