So first off, what is autoimmune disease? Autoimmune disease a condition in which the body’s immune system mistakenly attacks the body itself.
Thus far, more than 80 different autoimmune diseases have been identified, with some of the most prevalent including rheumatoid arthritis, Crohn’s disease, type 1 diabetes, and multiple sclerosis . Autoimmune disease is one of the top ten causes of death in women under the age of 65 and is the second highest cause of chronic illness in America . These diseases are often life-limiting, debilitating, and if left untreated can become life threatening. Current estimates indicate that roughly 50 million people in the United States are afflicted with an autoimmune disease and this represents a substantial economic burden in this country costing more than $100 billion dollars in annual healthcare costs . And unlike other conditions such as cancer, there is currently no cure for autoimmune disease and treatment options are very limited.
Since their inception, chimeric antigen receptor T-cell (CAR-T) therapies have undergone extensive study and refinement. The potential of these therapies was realized in 2017 when two CAR-T cell therapies, Yescarta (TM) and Kymriah (TM), were approved for clinical use to treat CD19+ B-cell lymphoma . The knowledge gained and lessons learned in the development of these therapies has helped define the potential of CAR-T and it is now clear these cells have clinical relevance far beyond cancer therapy [4,5].
The prevalence of autoimmune diseases is on the rise [7-9]. Modern hygiene and disinfection practices have reduced our interactions with microorganisms which are critical for teaching our immune system the difference between foreign and self to prevent autoimmune reactions . Because hygiene standards are unlikely to change anytime soon, the global market for autoimmune therapies is predicted to reach $153.32 billion by 2025.10 Current treatments for autoimmune diseases are immunomodulating or anti-inflammatory small molecules or proteins designed to help reduce symptoms [11–13]. While these options do provide relief for many patients, they have significant limitations including treatment resistance, continuous administration requirements, and significant side effects [11–15] For many autoimmune conditions such as multiple sclerosis, treatments are unable to prevent the inevitable disease progression leaving those suffering in dire need of a better solution . Due to the significant role of T-cells in autoimmunity, CAR-T based approaches for these ailments have the potential to deliver solutions which can provide long term benefit for patients in the form of symptom reduction, tissue repair, and perhaps a cure [5,6,14,17].
T-cell biology is complex, but two classes of T-cells seem to stand out for their potential in autoimmune CAR-T therapies. Effector T-cells (Teff) are responsible for defending our body against pathogens and cancer . They do this by directly killing foreign or defective cells and releasing inflammatory factors [18,19]. On the other hand, regulatory T-cells (Treg) are responsible for suppressing an immune response to minimize harm to self. This is achieved by releasing immunosuppressive cytokines and the suppression of autoreactive immune cell populations [5,6,17,19]. When this system functions properly, it allows the body to provide a strong defense against foreign challengers while minimizing the damage to self. However, an imbalance of one of these subsets can cause or accelerate disease [17,10]. In the case of many autoimmune conditions, the balance tips in favor of Teff cells and leads to the production of inflammation and autoantibodies [14,17].
Currently, two strategies are the frontrunners for autoimmune CAR-Ts. The first involves a strategy similar to how clinically approved CAR-T therapies function. Teff cells are engineered to possess a chimeric antigen receptor (CAR) with an extracellular component that resembles the self-antigen that the autoantibodies bind to. This allows these CAR-T cells to identify and destroy B-cells producing harmful autoantibodies [6,14]. This efficacy of this approach has been tested in preclinical animal models and shown tremendous benefit for a number of autoimmune diseases including pemphigus vulgaris  and lupus [14,22] and has progressed to a Phase I clinical trial (NCT03030976). Due to its similarity to clinically approved CAR-T therapies, this strategy will likely be the first to make it to market. However, these cells may carry similar risks of cytokine release syndrome and neurotoxicity or therapeutic exhaustion over time which may limit their use .
Computational fluid dynamic simulation of in-chip microfluidic vortex shedding .
About the Author
Michael A. Evans, BSci MSci is a bioengineering Ph.D. candidate at Harvard University with 7 years of experience in immunology, cell therapies, drug delivery, and organic chemistry. His current research focuses on using macrophages as carriers for nanoparticles to improve their targeting towards inflamed tissues. He is an author of 4 peer reviewed publications with three more in press. He attended Furman University and the University of California Santa Barbara (UCSB), where he received a B.S. and M.S. in chemistry, respectively. He received the 2014 John Sampey Award for the Chemical Sciences and was a 2017 UCSB New Venture Competition Finalist and the People’s Choice Award recipient. Michael will be finishing his PhD in late 2019 and is excited to begin his career in gene-modified cell therapy.
- Yip, A. & Webster, R. M. The market for chimeric antigen receptor T cell therapies.Nat. Rev. Drug Discov.17, 161–162 (2018).
- Bluestone, J. A. & Tang, Q. T reg cells—the next frontier of cell therapy.Science (80-. ).362, 154–155 (2018).
- Maldini, C. R., Ellis, G. I. & Riley, J. L. CAR T cells for infection, autoimmunity and allotransplantation.Nat. Rev. Immunol.18, 605–616 (2018).
- Cooper, G. S., Bynum, M. L. K. & Somers, E. C. Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases.J. Autoimmun.33, 197–207 (2009).
- Okada, H., Kuhn, C., Feillet, H. & Bach, J. F. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: An update.Clin. Exp. Immunol.160, 1–9 (2010).
- Bach, J. F. The hygiene hypothesis in autoimmunity: The role of pathogens and commensals.Nat. Rev. Immunol.18, 105–120 (2018).
- Correa, D. Global Autoimmune Disease Therapeutics Market to Garner $ 153.32 Billion by 2025 at 4.2 % CAGR,Says Allied Market Research.Global News Wire(2019). Available at: https://www.globenewswire.com/news-release/2019/03/13/1752518/0/en/Global-Autoimmune-Disease-Therapeutics-Market-to-Garner-153-32-Billion-by-2025-at-4-2-CAGR-Says-Allied-Market-Research.html. (Accessed: 5th December 2019)
- Chan, A. C. & Carter, P. J. Therapeutic antibodies for autoimmunity and inflammation.Nat. Rev. Immunol.10, 301–316 (2010).
- Olivera, P., Danese, S. & Peyrin-biroulet, L. Next generation of small molecules in inflammatory bowel disease.Gut66, 199–209 (2017).
- Hall, B. M., Hodgkinson, S. J. & Quin, J. Corticosteroids in autoimmune diseases.Australian Prescriber(1999).
- Tahir, A. Is Chimeric Antigen Receptor T-cell Therapy the Future of Autoimmunity Management?Cureus10, 3–5 (2018).
- Pichler, W. J. & Campi, P.Adverse side effects to biological agents.Drug Hypersensitivity(2007).
- Wingerchuk, D. M. & Weinshenker, B. G. Disease modifying therapies for relapsing multiple sclerosis.BMJ354, (2016).
- Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance.Cell133, 775–787 (2008).
- Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. J.Immunobiology: The Immune System in Health and Disease.Garland Science(2001).
- Pennock, N. D.et al.T cell responses: naïve to memory and everything in between.Adv. Physiol. Educ.37, 273–283 (2013).
- Ward-Hartstonge, K. A. & Kemp, R. A. Regulatory T-cell heterogeneity and the cancer immune response.Clin. Transl. Immunol.6, e154 (2017).
- Ellebrecht, C. T.et al.Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.Science (80-. ).353, 179–184 (2016).
- Leick, M. B. & Maus, M. V. CAR-T cells beyond CD19, UnCAR-Ted territory.Am. J. Hematol.34–41 (2019). doi:10.1002/ajh.25398
- Elinav, E., Waks, T. & Eshhar, Z. Redirection of Regulatory T Cells With Predetermined Specificity for the Treatment of Experimental Colitis in Mice.Gastroenterology134, 2014–2024 (2008).
- Blat, D., Zigmond, E., Alteber, Z., Waks, T. & Eshhar, Z. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells.Mol. Ther.22, 1018–1028 (2014).
- Fransson, M.et al.CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery.J. Neuroinflammation9, 1 (2012).
- Broady, R.et al.Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor.J. Clin. Invest.126, 1413–1424 (2016).
- Piscopo, N. J.et al.Bioengineering Solutions for Manufacturing Challenges in CAR T Cells.Biotechnol. J.13, 1–10 (2018).
- Jarrell, J. A.et al.Intracellular delivery of mRNA to human primary T cells with microfluidic vortex shedding.Sci. Rep.9, 1–11 (2019).
- Zhang, M.et al.The impact of Nucleofection® on the activation state of primary human CD4 T cells.J. Immunol. Methods408, 123–131 (2014).