Immunotherapy Strategy for Systemic Autoimmune Diseases: Comparison
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Systemic autoimmune diseases (SAIDs), such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and rheumatoid arthritis (RA), are fully related to the unregulated innate and adaptive immune systems involved in their pathogenesis. They have similar pathogenic characteristics, including the interferon signature, loss of tolerance to self-nuclear antigens, and enhanced tissue damage like necrosis and fibrosis. Glucocorticoids and immunosuppressants, which have limited specificity and are prone to tolerance, are used as the first-line therapy. A plethora of novel immunotherapies have been developed, including monoclonal and bispecific antibodies, and other biological agents to target cellular and soluble factors involved in disease pathogenesis, such as B cells, co-stimulatory molecules, cytokines or their receptors, and signaling molecules. Many of these have shown encouraging results in clinical trials. CAR-T cell therapy is considered the most promising technique for curing autoimmune diseases, with recent successes in the treatment of SLE and SSc.

  • immunotherapy
  • autoimmune diseases
  • CAR-T cells
  • systemic lupus erythematosus (SLE)
  • systemic sclerosis (SSc)
  • rheumatoid arthritis (RA)

1. Introduction

Approximately 5–10% of the world’s population suffers from autoimmune diseases [1]. In these patients, a highly complex network of cytokines and their receptors on immune cells destroys healthy tissues and becomes overactive. Many various physiological systems, including the skin, joints, kidneys, lungs, heart and blood cells, might be affected by the symptoms of these disorders. Conventional treatment, mainly glucocorticoids and immunosuppressants, has long been the mainstay of therapy for both moderate and severe disease, but has poor results and low specificity [2]. Among patients, there are many who suffer from the side effects of this type of therapy, as they are forced to take medication for many years [3]. It was not until 2011 that the US Food and Drug Administration (FDA) authorized the first biological drug (belimumab) for the treatment of people with active SLE [4].
Particularly for individuals who do not react to traditional therapies, targeted therapy has recently become a more promising option [5]. Novel biological agents with different mechanisms of action, including monoclonal (mAb) and bispecific antibodies (BsAb), can target B cells, co-stimulatory molecules, and cytokines or their receptors, demonstrating their clinical efficacy and safety [6,7][6][7]. Some agents, such as rituximab, tocilizumab, anifrolumab and abatacept, have shown activity in several autoimmune diseases, including SLE, SSc and RA, and are currently in clinical trials. Furthermore, the main aspects of the pathogenesis of SAIDs, including the inhibition of regulatory or cytotoxic T cells and the activation and proliferation of autoreactive B cells, suggest the possibility of therapeutic application of chimeric antigen receptor T (CAR-T) cells to treat autoreactive immune cells.
Some researchers also believe that, in addition to environmental and genetic factors, the gut microbiota is responsible for the pathogenesis of SAIDs [8]. Therefore, in addition to traditional treatments with immunosuppressants and glucocorticoids, as well as more effective approaches associated with the use of biological drugs and CAR-T therapy, there is a view that successful treatment requires measures to correct the intestinal microbiota [9].
At present, CAR-T cell therapy is realizing its potential mainly in oncology, but some progress has also been made in the treatment of SAIDs. According to recent evidence, treating SLE using CD19 CAR-T cells is a viable and highly effective process [10]. Similar data were obtained in patients with severe systemic sclerosis, demonstrating the high potential of this method in clinical practice [11]. Progress in manufacturing CAR-T and other cell immunotherapies has allowed the obtainment of more affordable products for both cancer and autoimmune diseases [12]. Recent developments in CAR-T therapy are anticipated to usher in a new age of autoimmune disease treatment. 

2. Common Therapeutics for SLE, SSc and RA

Some biological agents, such as rituximab, abatacept, anifrolumab and tocilizumab, have been shown to be effective in several SAIDs, including SLE, SSc and RA, discussed above, and are currently in clinical trials (Figure 1). The first on this list is rituximab. It is a chimeric anti-CD20 mAb that eliminates autoreactive B cells and a subset of T cells, thereby reducing antibody production [113][13]. Rituximab has demonstrated efficacy in patients with RA and was approved by the FDA in 2006 for the treatment of RA [102][14]. However, its efficacy in SLE has not been clearly demonstrated, and future studies are needed to clarify its efficacy in this disease [62,63][15][16]. Rituximab showed clear promise in SSc in the first randomized controlled trials, acting on the skin as well as the lungs [114,115,116][17][18][19]. However, the long-term efficacy of this drug in the treatment of patients with SSc is still controversial and needs to be clarified [117][20]. Clinical trials of the drug have already reached Phase IV in SLE and Phase III in SSc. Adding belimumab after rituximab in a special trial of SLE therapy significantly reduced the risk of severe flares and serum IgG anti-dsDNA antibody levels, suggesting that combining these drugs could be a promising therapeutic strategy [41][21]. The combination of belimumab and rituximab is also being studied in a Phase II trial in SSc patients (NCT03844061).
Figure 1. The basic common targets for the treatment of SLE, SSc and RA with biological agents. Rituximab is chimeric anti-CD20 mAb, which eliminates autoreactive B cells and a subset of T cells. Abatacept is a fusion protein, a soluble CTLA-4 analog, that inhibits T cell activation by binding to CD80 and CD86 receptors on APC, selectively blocking the specific interaction of CD80/CD86 receptors to CD28 and, therefore, inhibiting T cell proliferation and B cell immunological response. Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1κ) mAb that selectively binds to subunit 1 of INFAR1, inhibiting receptor activity and reducing downstream signaling and gene transcription of inflammatory mediators. Tocilizumab is an anti-IL-6R mAb that binds soluble and membrane-bound IL-6 receptors, preventing IL-6 mediated inflammation. The use of CAR-T cells targeting CD19 is the most promising approach for treatment of SLE, SSc and RA.
B cell activation is regulated by the interaction of co-stimulatory signals with T cells when CD28, which is constitutively expressed on T cells, binds to CD80/CD86 on antigen presenting cells (APCs). At the same time, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) was found to compete with CD28 for CD80/CD86 binding, and an increase in CTLA-4 expression on the activated T cell provides negative signals for T cell activation [118][22]. This approach is currently being used to target SAIDs, including SLE, SSc and RA (Figure 1). For example, the fusion protein abatacept, a soluble CTLA-4 analogue, acts as an antagonist of CD28-mediated co-stimulation to prevent the specific interaction of CD28 with CD80/CD86, resulting in inhibition of B-cell growth and activation. Abatacept has been shown in long-term studies to be a well-tolerated drug with an acceptable and consistent safety profile for the treatment of RA. Immunogenicity rates are low and transient and do not interfere with clinical response or safety [119][23]. And so, the FDA approved it for RA in 2005. Abatacept has demonstrated efficacy and an acceptable safety profile in the treatment of SLE patients [120][24]. This drug is also being studied for the therapy of SSc and is currently in clinical trials (Phase II), in which it has showed some improvement in skin fibrosis and MRSS score [121,122][25][26].
Type 1 INF (IFNα) has also been shown to play an important role in the pathogenesis of SAIDs and is of increasing interest to researchers as a therapeutic target (Figure 1) [30,123,124][27][28][29]. Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1κ) mAb that targets subunit 1 of INFAR1 and therefore blocks IFN-α and IFN-β signaling [124][29]. A meta-analysis of four study databases evaluating the safety of anifrolumab versus placebo in SLE patients clearly demonstrated the tolerability and efficacy of this antibody [125][30]. As a result, anifrolumab was approved for clinical use first in the United States in July 2021 and then in the European Union in February 2022 for the treatment of SLE. Anifrolumab is currently in Phase III clinical trials for this disease. In SSc, blocking the IFN signaling pathway has been suggested to reduce fibrosis and inflammation and may therefore be a target [93][31]. Similar to SLE, anifrolumab has shown efficacy in the treatment of SSc and is now in a Phase III clinical trial. Clinical trials for RA reported that future larger studies are needed to assess the efficacy of this drug in RA [123,126][28][32].
Tocilizumab is an anti-IL-6R mAb that binds soluble and membrane-bound IL-6 receptors and prevents IL-6-mediated inflammation (Figure 1). This antibody has shown some efficacy in patients with refractory RA [127][33]. In addition, tocilizumab monotherapy has been shown to be more effective in the treatment of RA than treatment with adalimumab, a TNF-α antagonist [128][34]. Based on its efficacy, tocilizumab was approved for the treatment of RA in Japan in 2008, in the European Union in 2009 and in the United States in 2010. The efficacy of tocilizumab in SSc was confirmed in Phase III clinical trials [129,130][35][36]. Tocilizumab is currently in Phase I clinical trials for SLE. Preliminary data have shown that tocilizumab may be a good alternative treatment for patients with SLE who do not respond to high-dose glucocorticoids, but further studies are needed [131,132][37][38].
CAR-T therapy is the most advanced and promising approach for the treatment of SLE, SSc and RA, and after appropriate research and refinement, any of the described cell types (anti-CD19 CAR-T, cCAR-T, CAAR-T and CAR-Treg) may be applicable (Figure 1).

References

  1. Wang, L.; Wang, F.; Gershwin, M.E. Human Autoimmune Diseases: A Comprehensive Update. J. Intern. Med. 2015, 278, 369–395.
  2. Dima, A.; Jurcut, C.; Arnaud, L. Hydroxychloroquine in Systemic and Autoimmune Diseases: Where Are We Now? Jt. Bone Spine 2021, 88, 105143.
  3. Emamikia, S.; Gentline, C.; Chatzidionysiou, K.; Arnaud, L.; van Vollenhoven, R. Relationship between Glucocorticoid Dose and Adverse Events in Systemic Lupus Erythematosus: Data from a Randomized Clinical Trial. Scand. J. Rheumatol. 2018, 47, 131–140.
  4. Dubey, A.K.; Handu, S.S.; Dubey, S.; Sharma, P.; Sharma, K.K. Belimumab: First Targeted Biological Treatment for Systemic Lupus Erythematosus. J. Pharmacol. Pharmacother. 2011, 2, 317–319.
  5. Felten, R.; Dervovic, E.; Chasset, F.; Gottenberg, J.-E.; Sibilia, J.; Scher, F.; Arnaud, L. The 2018 Pipeline of Targeted Therapies under Clinical Development for Systemic Lupus Erythematosus: A Systematic Review of Trials. Autoimmun. Rev. 2018, 17, 781–790.
  6. Hafeez, U.; Gan, H.K.; Scott, A.M. Monoclonal Antibodies as Immunomodulatory Therapy against Cancer and Autoimmune Diseases. Curr. Opin. Pharmacol. 2018, 41, 114–121.
  7. Zhao, Q. Bispecific Antibodies for Autoimmune and Inflammatory Diseases: Clinical Progress to Date. BioDrugs 2020, 34, 111–119.
  8. Kalayci, F.N.C.; Ozen, S. Possible Role of Dysbiosis of the Gut Microbiome in SLE. Curr. Rheumatol. Rep. 2023, 25, 247–258.
  9. Pan, Q.; Guo, F.; Huang, Y.; Li, A.; Chen, S.; Chen, J.; Liu, H.; Pan, Q. Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus: Novel Insights into Mechanisms and Promising Therapeutic Strategies. Front. Immunol. 2021, 12, 799788.
  10. Mackensen, A.; Müller, F.; Mougiakakos, D.; Böltz, S.; Wilhelm, A.; Aigner, M.; Völkl, S.; Simon, D.; Kleyer, A.; Munoz, L.; et al. Anti-CD19 CAR T Cell Therapy for Refractory Systemic Lupus Erythematosus. Nat. Med. 2022, 28, 2124–2132.
  11. Bergmann, C.; Müller, F.; Jörg, D.; Györfi, D.M.H.; Völkl, S.; Aigner, M.; Harrer, T.; Bayerl, N.; Atzinger, A.; Taubmann, J.; et al. AB0816 Treatment of a Patient with Severe Diffuse Systemic Sclerosis (SSC) Using CD19-Targeting CAR-T-Cells. In Scientific Abstracts; BMJ Publishing Group Ltd.: London, UK; European League Against Rheumatism: Zürich, Switzerland, 2023; p. 1621.
  12. Ganeeva, I.; Zmievskaya, E.; Valiullina, A.; Kudriaeva, A.; Miftakhova, R.; Rybalov, A.; Bulatov, E. Recent Advances in the Development of Bioreactors for Manufacturing of Adoptive Cell Immunotherapies. Bioengineering 2022, 9, 808.
  13. Kaegi, C.; Wuest, B.; Schreiner, J.; Steiner, U.C.; Vultaggio, A.; Matucci, A.; Crowley, C.; Boyman, O. Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders. Front. Immunol. 2019, 10, 1990.
  14. Edwards, J.C.W.; Szczepański, L.; Szechiński, J.; Filipowicz-Sosnowska, A.; Emery, P.; Close, D.R.; Stevens, R.M.; Shaw, T. Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis. N. Engl. J. Med. 2004, 350, 2572–2581.
  15. Merrill, J.T.; Neuwelt, C.M.; Wallace, D.J.; Shanahan, J.C.; Latinis, K.M.; Oates, J.C.; Utset, T.O.; Gordon, C.; Isenberg, D.A.; Hsieh, H.-J.; et al. Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus: The Randomized, Double-Blind, Phase Ii/Iii Systemic Lupus Erythematosus Evaluation of Rituximab Trial. Arthritis Rheum. 2010, 62, 222–233.
  16. Kamburova, E.G.; Koenen, H.J.P.M.; Borgman, K.J.E.; ten Berge, I.J.; Joosten, I.; Hilbrands, L.B. A Single Dose of Rituximab Does Not Deplete B Cells in Secondary Lymphoid Organs but Alters Phenotype and Function. Am. J. Transplant. 2013, 13, 1503–1511.
  17. Maher, T.M.; Tudor, V.A.; Saunders, P.; Gibbons, M.A.; Fletcher, S.V.; Denton, C.P.; Hoyles, R.K.; Parfrey, H.; Renzoni, E.A.; Kokosi, M.; et al. Rituximab versus Intravenous Cyclophosphamide in Patients with Connective Tissue Disease-Associated Interstitial Lung Disease in the UK (RECITAL): A Double-Blind, Double-Dummy, Randomised, Controlled, Phase 2b Trial. Lancet Respir. Med. 2023, 11, 45–54.
  18. Ebata, S.; Yoshizaki, A.; Oba, K.; Kashiwabara, K.; Ueda, K.; Uemura, Y.; Watadani, T.; Fukasawa, T.; Miura, S.; Yoshizaki-Ogawa, A.; et al. Safety and Efficacy of Rituximab in Systemic Sclerosis (DESIRES): A Double-Blind, Investigator-Initiated, Randomised, Placebo-Controlled Trial. Lancet Rheumatol. 2021, 3, e489–e497.
  19. Morgan, K.; Woollard, C.; Beinart, D.; Host, L.V.; Roddy, J. Rituximab Treatment for Systemic Sclerosis-associated Interstitial Lung Disease: A Case Series of 13 Patients. Intern. Med. J. 2023, 53, 1147–1153.
  20. Yoshifuji, H.; Yomono, K.; Yamano, Y.; Kondoh, Y.; Yasuoka, H. Role of Rituximab in the Treatment of Systemic Sclerosis: A Literature Review. Mod. Rheumatol. 2023, 33, 1068–1077.
  21. Shipa, M.; Embleton-Thirsk, A.; Parvaz, M.; Santos, L.R.; Muller, P.; Chowdhury, K.; Isenberg, D.A.; Doré, C.J.; Gordon, C.; Ehrenstein, M.R. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus. Ann. Intern. Med. 2021, 174, 1647–1657.
  22. Rowshanravan, B.; Halliday, N.; Sansom, D.M. CTLA-4: A Moving Target in Immunotherapy. Blood 2018, 131, 58–67.
  23. Pombo-Suarez, M.; Gomez-Reino, J.J. Abatacept for the Treatment of Rheumatoid Arthritis. Expert Rev. Clin. Immunol. 2019, 15, 319–326.
  24. Pimentel-Quiroz, V.R.; Ugarte-Gil, M.F.; Alarcón, G.S. Abatacept for the Treatment of Systemic Lupus Erythematosus. Expert Opin. Investig. Drugs 2016, 25, 493–499.
  25. Chung, L.; Spino, C.; McLain, R.; Johnson, S.R.; Denton, C.P.; Molitor, J.A.; Steen, V.D.; Lafyatis, R.; Simms, R.W.; Kafaja, S.; et al. Safety and Efficacy of Abatacept in Early Diffuse Cutaneous Systemic Sclerosis (ASSET): Open-Label Extension of a Phase 2, Double-Blind Randomised Trial. Lancet Rheumatol. 2020, 2, e743–e753.
  26. Khanna, D.; Spino, C.; Johnson, S.; Chung, L.; Whitfield, M.L.; Denton, C.P.; Berrocal, V.; Franks, J.; Mehta, B.; Molitor, J.; et al. Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. Arthritis Rheumatol. 2020, 72, 125–136.
  27. Bezalel, S.; Guri, K.M.; Elbirt, D.; Asher, I.; Sthoeger, Z.M. Type I Interferon Signature in Systemic Lupus Erythematosus. Isr. Med. Assoc. J. 2014, 16, 246–249.
  28. Lin, C.M.A.; Isaacs, J.D.; Cooles, F.A.H. Role of IFN-α in Rheumatoid Arthritis. Curr. Rheumatol. Rep. 2024, 26, 37–52.
  29. Casey, K.A.; Guo, X.; Smith, M.A.; Wang, S.; Sinibaldi, D.; Sanjuan, M.A.; Wang, L.; Illei, G.G.; White, W.I. Type I Interferon Receptor Blockade with Anifrolumab Corrects Innate and Adaptive Immune Perturbations of SLE. Lupus Sci. Med. 2018, 5, e000286.
  30. Liu, Z.; Cheng, R.; Liu, Y. Evaluation of Anifrolumab Safety in Systemic Lupus Erythematosus: A Meta-Analysis and Systematic Review. Front. Immunol. 2022, 13, 996662.
  31. Kakkar, V.; Assassi, S.; Allanore, Y.; Kuwana, M.; Denton, C.P.; Khanna, D.; Del Galdo, F. Type 1 Interferon Activation in Systemic Sclerosis: A Biomarker, a Target or the Culprit. Curr. Opin. Rheumatol. 2022, 34, 357–364.
  32. Tovey, M.G.; Lallemand, C. Immunogenicity and Other Problems Associated with the Use of Biopharmaceuticals. Ther. Adv. Drug Saf. 2011, 2, 113–128.
  33. Maini, R.N.; Taylor, P.C.; Szechinski, J.; Pavelka, K.; Bröll, J.; Balint, G.; Emery, P.; Raemen, F.; Petersen, J.; Smolen, J.; et al. Double-blind Randomized Controlled Clinical Trial of the Interleukin-6 Receptor Antagonist, Tocilizumab, in European Patients with Rheumatoid Arthritis Who Had an Incomplete Response to Methotrexate. Arthritis Rheum. 2006, 54, 2817–2829.
  34. Gabay, C.; Emery, P.; van Vollenhoven, R.; Dikranian, A.; Alten, R.; Pavelka, K.; Klearman, M.; Musselman, D.; Agarwal, S.; Green, J.; et al. Tocilizumab Monotherapy versus Adalimumab Monotherapy for Treatment of Rheumatoid Arthritis (ADACTA): A Randomised, Double-Blind, Controlled Phase 4 Trial. Lancet 2013, 381, 1541–1550.
  35. Khanna, D.; Lin, C.J.F.; Furst, D.E.; Wagner, B.; Zucchetto, M.; Raghu, G.; Martinez, F.J.; Goldin, J.; Siegel, J.; Denton, C.P. Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis–Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial. Am. J. Respir. Crit. Care Med. 2022, 205, 674–684.
  36. Roofeh, D.; Lin, C.J.F.; Goldin, J.; Kim, G.H.; Furst, D.E.; Denton, C.P.; Huang, S.; Khanna, D. Tocilizumab Prevents Progression of Early Systemic Sclerosis–Associated Interstitial Lung Disease. Arthritis Rheumatol. 2021, 73, 1301–1310.
  37. Chaoyi, M.; Shrestha, B.; Hui, L.; Qiujin, D.; Ping, F. Tocilizumab Therapy for Persistent High-Grade Fever in Systemic Lupus Erythematosus: Two Cases and a Literature Review. J. Int. Med. Res. 2022, 50, 030006052210885.
  38. Yadav, S.; Sharma, V.; Balakrishnan, C. Tocilizumab Therapy for Treatment-Resistant Systemic Lupus Erythematosus with Elevated IL-6 and CRP Levels: A Case Report. SN Compr. Clin. Med. 2023, 5, 199.
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