Abstract
Various pathologies caused by a dysregulated immune system characterized by chronic inflammation leading to pain or permanent damage to tissue are grouped under an umbrella term “autoimmune disorders.” Immunotherapy is a field of immunology that facilitates discovery of therapies for diseases by means of stimulation, augmentation, or suppression of an immunoresponse. Several emerging and promising next-generation immunotherapy modalities for autoimmune diseases such as checkpoint based immunotherapy, antigen-specific immunotherapies, anti-cytokine therapy, anti-T-cell therapy, anti-B-cell therapy and biologics and their combination therapy, etc., have evolved and initiated the new era of immunotherapy for autoimmune diseases in the recent past. We discuss these modalities in detail along with comprehensive tables that elucidate the specific therapies. Further, we delineate current immunotherapeutics in clinical trials for autoimmune diseases and discuss the “financial toxicity” of current immunotherapies in autoimmune diseases.
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Keywords
- Immunotherapy
- Autoimmune diseases
- Checkpoint immunotherapy
- Antigen-specific immunotherapy
- Anti-cytokine therapy
- Anti-T-cell therapy
- Anti-B-cell therapy
- Biologics
- Clinical trials
- Financial toxicity
4.1 The Immune System: An Overview
The human immune system is a complicated set of cellular and molecular mechanisms involving different proteins and biochemicals, which protects the human body against infectious pathogens, cancer cells, and alien substances without attacking the endogenous molecules. The protection of the host body against all types of infections by specifically recognizing and eliminating foreign agents is the prime function of the immune system (Viswanath 2013). In general, the immune system has two lines of defense: innate immunity and adaptive immunity. The first immunological, antigen-independent (non-specific) mechanism for combating an intruding pathogen is innate immunity. It is a rapid immune response which occurs within minutes or hours after attack. The innate immune response has no immunologic memory and, therefore, is unable to recognize or “memorize” the same pathogen when the body gets exposed to it in the future. Various cells are employed in the innate immune response such as phagocytes (macrophages and neutrophils), dendritic cells, mast cells, basophils, eosinophils, natural killer (NK) cells, and lymphocytes (T-cells) as well as complement system (Warrington et al. 2011). Both types of phagocytes act by a similar mechanism of engulfing the microbes. Besides this similar function, neutrophils release their specific granules which assist in the elimination of pathogenic microbes and macrophages also play an important role in antigen presentation to T-cells. Dendritic cells act as important messengers between innate and adaptive immunity by their ability to phagocytose and function as antigen-presenting cells (APCs). Both mast cells (which reside in the connective tissue surrounding blood vessels) and basophils (which reside in the circulation) are involved in the initiation of acute inflammatory responses, such as those seen in allergy and asthma. Eosinophils are granulocytes that possess phagocytic properties and play an important role in the destruction of large parasites which are difficult to phagocytose. NK cells also known as large granular lymphocytes (LGLs) play a major role in the rejection of tumors and the destruction of cells infected by viruses which is achieved through the release of perforins and granzymes from NK-cell granules which induce apoptosis (programmed cell death) (Stone et al. 2010). On the other hand, adaptive immunity is antigen-dependent and antigen-specific due to which it involves a lag time between exposure to the antigen and maximal response. When infection is established due to the inability of innate immunity to effectively eliminate infectious agents, adaptive immunity develops. The main characteristic feature of adaptive immunity is its ability to memorize the initial immunologic response which endows the host to generate a more rapid and efficient immune response upon subsequent exposure to the antigen. The most important functions of the adaptive immune response are the detection of specific “non-self” antigens in the presence of “self” antigens; the activation of pathogen-specific immunologic effector pathways that eradicate specific pathogens or pathogen-infected cells; and the development of an immunologic memory that can promptly eliminate a specific pathogen when subsequent infections occur in future (Warrington et al. 2011). Adaptive responses are of two types: cell-mediated immunity, conducted by T-cells and facilitated by APCs; and humoral immunity (antibody-mediated immunity), mediated by antibodies produced by B-cells. The T lymphocytes account for 60–80% of total lymphocytes and have a very high lifetime. They primarily eradicate the intracellular pathogens by activating macrophages and kill virally infected cells by recognizing the primary structure of an antigen. T helper (Th) lymphocytes represent 2/3 of total lymphocytes and secrete interleukins (messenger molecules that assist the communications between immune system cells). Depending on the type of cytokines secreted, two types of Th cells are distinguished: Th1 cells which produce interleukin-2, IFN-γ, and TNF-α and trigger inflammatory reactions; and Th2 cells which produce interleukins 3, 4, and 5. In humoral immunity, activation of B lymphocytes results into the synthesis of antigen-specific immunoglobulins (antibodies) by plasma cells and development of immunological memory by memory B-cells (Grigore and Inform 2017). In conclusion, the tightly regulated interplay between T-cells, B-cells, and APCs play a significant role(s) in the development of adaptive immunity in concurrence with innate immunity to eradicate infectious agents. Thus, defects in either system can lead to immune pathological disorders such as hypersensitivity reactions, autoimmune diseases, and immunodeficiencies (Warrington et al. 2011).
4.2 Autoimmunity and Immune Tolerance
In simple words, the defect in the host’s immune system that results in loss of normal immune homeostasis and produces an abnormal response to its own tissues is referred to as autoimmunity. The presence of self-reactive T-cells, auto-antibodies, and inflammation are the hallmarks of the autoimmunity (Warrington et al. 2011). The Nobel Prize-winning hypothesis of the “forbidden clone” by Macfarlane Burnet led to a better understanding of not only autoimmunity but also of lymphoid cell development, thymic education, apoptosis, and deletion of autoreactive cells and mechanisms of autoimmunity that led to clinical disease (Wang et al. 2015). Thus, autoimmunity is considered to be an interruption in the process of antigenic detection and elimination. Body’s cells may undergo antigenic variation as a result of physical, chemical, or biological influences. Such “neo-antigens” (altered antigens) may elicit an immune response that destroys body’s own cells (Ganapathy et al. 2017). Thus, autoimmunity may also be defined as the genesis of immune system reactivity via autoantibodies or T-cell responses to self-structures (Viswanath 2013).
The concept of immune tolerance was defined as an ability of the immune system to prevent itself from targeting self-molecules, cells, or tissues (Wang et al. 2014). During maturation of the immune system, it becomes “tolerant” to self by eliminating the immune cells that react against self-tissues. To understand immune tolerance, it is important to realize the key concepts such as central tolerance, peripheral anergy, T regulatory cells (Tregs), and the homeostasis produced by cytokines and chemokines and their cognate receptors. During central tolerance in the thymus, developing lymphocytes go through positive selection in the cortex prior to maturing and entering the circulation while lymphocytes with impending reactivity against self-peptides are negatively selected and deleted in the thymic medulla. After leaving the thymus, mature T-cells undergo secondary selection (peripheral tolerance) by which the majority of self-reactive T-cells are deleted or rendered anergic. Further in the process of clonal deletion or clonal anergy, immature B-cells expressing surface immunoglobulin M (IgM) capable of recognizing ubiquitous self cell surface antigens are eliminated. Even though mature B-cells are under the control of peripheral tolerance, with the help of process known as clonal deletion or clonal anergy, autoreactive B-cells can escape deletion (Wang et al. 2015; Salinas et al. 2013). It is important to note that, in normal individuals also, potentially self-reacting lymphocytes can still “leak out” in small numbers into the periphery, even under the strict surveillance of central and peripheral tolerance. Thus, depending upon the existence of self-reactive T and B lymphocytes and their abilities to produce autoantibodies, autoimmunity can be classified as “physiological” and “pathological” autoimmunity (Avrameas and Selmi 2013). Physiological autoimmunity is generally staged without evidence of clinical disease where natural autoantibodies help to maintain normal immune homeostasis by eliminating self and foreign antigens. On the other hand, pathological autoimmunity is a stage that develops when immune tolerance is broken and autoantibodies and self-reactive lymphocytes become involved in inflammation which further lead to development of autoimmune diseases (Wang et al. 2015).
4.3 Autoimmune Diseases
The breach of immune tolerance, i.e. the failure to differentiate self from non-self, leading to the development of autoimmunity is the basis for autoimmune diseases. Various pathologies caused by a dysregulated immune system characterized by chronic inflammation leading to pain or permanent damage to tissue are grouped under an umbrella term “autoimmune disorders.” In simple words, autoimmune diseases are the variety of diseases arising due to the irregular functioning of the immune system, that leads to the generation of immune system reactivity (Viswanath 2013). Indeed, autoimmune diseases are multi-etiological entities that develop due to disturbed immunoregulatory processes, as well as environmental and genetic abnormalities. Heredity accounts for about 30% of the risk of developing an autoimmune disease, while non-inherited, environmental factors account for the remaining 70% risk (Viswanath 2013; Nagy et al. 2015). There is a permanent failure of one or several tolerance mechanisms in autoimmune diseases due to the cumulative effect of various specific human leukocyte antigen (HLA), non-HLA genes, and environmental factors and/or derailed immune regulatory processes. This leads to the development of self-reactive B- and T-cell clones, which cause damage to tissues or organs (Ermann and Fathman 2001). There are nearly 100 distinct autoimmune diseases, some of which are organ-specific such as primary biliary cirrhosis (PBC) and some of which reflect a variety of immunological dysfunction involving multiple organs such as systemic lupus erythematosus (SLE) (Wang et al. 2015; Yu et al. 2014). Thus, clinically autoimmune diseases can be classified as organ-specific (e.g., Type 1 diabetes mellitus) or systemic (e.g., systemic lupus erythematosus). The common types of autoimmune diseases such as Addison’s disease, autoimmune hepatitis, celiac disease, Type 1 diabetes, Grave’s disease (overactive thyroid), Guillain–Barre syndrome, Hashimoto’s disease, hemolytic anemia, inflammatory myopathies, idiopathic thrombocytopenic purpura, multiple sclerosis, myasthenia gravis, psoriasis, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, and vitiligo with their pathogenesis aspects are described elsewhere (Viswanath 2013; Wang et al. 2015).
A simple hypothesis for autoimmune diseases is that polymorphisms in various genes result in imperfect regulation or reduced threshold for lymphocyte activation, and environmental factors commence or enhance activation of self-reactive lymphocytes that have escaped control and are composed to react against self-constituents (Rosenblum et al. 2015). Autoimmune disorders are a group of diseases wherein structural/functional damage to cells/tissues/organs/organ systems is caused by the action of immunologically competent cells/antibodies against normal body constituents. To initiate autoimmunity several endocrine, genetic, and environmental factors interact together on immune system by the following mechanisms (Ganapathy et al. 2017; Wucherpfennig 2001):
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1.
Cytolysis of the target cells: Due to the release of tissue-specific autoantibodies via complement;
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Immune complex deposition: Due to the binding of auto-antibody to soluble mediators;
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Phagocytosis, cytotoxicity, and antibody-mediated cellular immunity: Due to the auto-antibody-mediated attack on immune system;
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Molecular Mimicry: Auto-antibody against foreign antigen and auto-antigen epitopes which mimic foreign antigen (cross reactive antigen) leading to tissue damage;
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5.
Stimulation/obstruction of the target structure: Due to the action on cell surface structures by autoantibodies.
Thus, the stimulation and maintenance of immune tolerance signify major therapeutic goals in autoimmunity-caused autoimmune diseases (Janikashvili et al. 2016).
4.4 Immunotherapy for Autoimmune Diseases: General Considerations
Immunotherapy is a field of immunology that facilitates discovery of therapies for diseases by means of stimulation, augmentation, or suppression of an immunoresponse. Simply, immunotherapy is a type of therapy which uses substances made by a body or in a laboratory to stimulate or suppress the immune system in order to improve or restore normal functions of the immune system, so that the body can effectively fight against cancer, infection, and other diseases. Immunotherapies capable of initiating or boosting the immune response are referred to as “activating immunotherapies,” while those capable of repressing the immune response are referred to as “suppressive immunotherapies” (Wraith 2017). More recently, the potential of immunotherapy to enhance or repress immune responses has been globally recognized and appreciated particularly in two areas of immunotherapy, i.e. suppressing immunotherapies for autoimmune diseases and activating immunotherapies for cancer. In the twenty-first century, the “immunotherapy revolution” started, with the approval of ipilimumab for melanoma. These cancer treatment approaches were based on activating immunotherapies which inhibit the inhibitors of the immune system releasing the brakes on the immune system. Subsequently, different immune checkpoint inhibitors, vaccines, and co-stimulatory agonists have been discovered and commercialized for a number of cancer types (Wraith 2017; De Miguel-Luken et al. 2017; Chen and Mellman 2013). On the other hand, the increased understanding of mechanisms of autoimmunity in recent years has paved the way to new promising therapeutic strategies for treating autoimmune diseases. This leads to the development of new types of immunotherapeutics that are capable of effectively and selectively targeting the self-reacting immune cells, cytokines, and other mediators of the immune response and are now available as cutting-edge therapies for autoimmune disease patients (Ostrov 2015).
The foremost challenge in the treatment of autoimmune diseases is to selectively suppress the autoimmune disease without affecting the control of rest of the functional immune system over cancers and infectious diseases. Hence, development of novel treatments with increasing specificity for the particular autoimmune disease is important with no or decreased risk of potential side effects (Wraith 2017). Historically in the 1980s, intra-venous immunoglobulin (IVIG) became a standard approach in managing autoimmune disorders, after the serendipitous discovery of polyclonal IgG immunoglobulin for the treatment of autoimmune thrombocytopenia (Imbach et al. 1981). After subsequent trials on many autoimmune disorders, greater than 70% of the IVIG prescribed in the United States by 2014 was for autoimmune and inflammatory diseases rather than for immunodeficiency (Ballow 2014). In recent years, further advancements in the research with various kinds of innovative work identifying new receptors, signaling pathways, monoclonal antibodies (MABs) and with the development of hybridomas and molecular cloning led to the discovery of new biologic agents directing the new treatments for autoimmune diseases (Ostrov 2015).
The current treatment strategies of autoimmune diseases include two major approaches, first is a “conservative approach” where a symptomatic or replacement therapy is given and second is an “aggressive approach” where immunosuppressive or immune modulation therapy is preferred. For instance, autoimmune thyroid disease is mainly managed either by reducing the production of thyroxin at the stage of hyper functioning of the thyroid gland or by hormone replacement therapy when the gland is damaged. On the other hand, in systemic diseases like SLE which targets vital organs like kidney, the primary treatment is immunosuppressive therapy in order to prevent more organ damage. Generally in autoimmune disease, 60–70% response is observed for immunosuppression with gradual decrease in the response to the drug used. Although in few cases there is a long-lasting remission of autoimmune diseases, some of the autoimmune diseases go for clinical remission to relapse after sometime (Chandrashekara 2012). It is important to note that currently available steroid and non-steroid immunosuppressive medicines for autoimmune diseases also have limited efficacy and we have been dependent on non-specific immunosuppressive therapies for quite some time (Wraith 2017). Hence, there is an immense need to develop new approaches and ways to modulate the immune system for developing new therapeutic strategies of immunotherapy for different autoimmune diseases. In the last few decades, significant advancements have occurred in the approaches of immunosuppressive therapy for autoimmune diseases. Compared to the initial immunosuppressive drugs which were non-specific and interfering with larger pathways and cells, current immunosuppressive drugs are more target-specific with profound immunosuppression effect, increased remission rate, and reduced toxicity on other collateral systems (Feldmann and Steinman 2005; Böhm et al. 2006). In recent years, several new types and therapeutic strategies of immunotherapy for autoimmune diseases have evolved. James P. Allison and Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine for the discovery of cancer therapy by inhibition of negative immunoregulation of CTLA4 and PD1 immune checkpoints. Immune checkpoint therapy has led to tremendous progress in clinical development and revolutionized cancer treatment. This seminal discovery has fundamentally improved the outcomes for many people with advanced cancer (Smyth and Teng 2018). Similarly, several emerging and promising next-generation immunotherapy modalities for autoimmune diseases such as checkpoint based immunotherapy, antigen-specific immunotherapies, anti-cytokine therapy, anti-T-cell therapy, anti-B-cell therapy and biologics and their combination therapy, etc., have evolved and initiated the new era of immunotherapy for autoimmune diseases over a past few decades. These modalities are being discussed in upcoming sections of this chapter.
4.5 Checkpoint-Based Immunotherapy for Autoimmune Diseases
As mentioned earlier, the important characteristic of an autoimmune disease is the induction of B-cell and T-cell autoreactivity directed against self proteins, i.e. autoantigens. In other words, self-tolerance is the unresponsiveness of the immune system to self-antigens, and dysregulation of immune homeostasis along with self-tolerance leads to autoimmunity, resulting in harmful inflammation in and destruction of autoantibodies generated by B-cells and self-tissues mediated by autoreactive T-cells (Zhang and Vignali 2016). During the T-cell development process, the majority of T-cells which are specific for self-antigens are erased or deleted in a process of thymic elimination to set up a focal tolerance prior to the entry of T-cells into the periphery (Hogquist et al. 2005). However, it is a known fact that, potentially self-reacting lymphocytes can still “leak out” in small numbers into the periphery, even under the strict surveillance of central and peripheral tolerance due to the incomplete thymic deletion process. Thus, in order to circumvent the attack on normal host cells by remaining self-specific T-cells, additional mechanisms are required. These mechanisms include inhibition of proliferation of self-antigen specific T-cells by development of regulatory T-cells (Tregs) and regulation of T-cell activation and their functions by development of checkpoint pathways. The peripheral tolerance mechanisms play a significant role in checking autoimmune diseases (He et al. 2017). According to the two-signal model, activation of native T-cells requires two signaling processes: stimulation by major histocompatibility complex (MHC)–peptide molecules of T-cell receptor (TCR), and co-stimulation on antigen-presenting cells (APCs) via co-stimulatory receptors and their corresponding ligands (Zhang and Vignali 2016). APCs express B7–1 (CD80) or B7–2 (CD86), the co-stimulatory molecules, which initiate the subsequent signals. T-cell co-stimulatory receptor CD28 recognizes these co-stimulating molecules and thus an engagement of both TCR and CD28 on same T-cells triggers their multiplication by prompting an initiating signal to the T-cells, leading to a T-cell response to a self-antigen (in autoimmunity) or a foreign antigen (He et al. 2017). On the other hand, the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) which is a T-cell receptor inhibitor, has a more prominent affinity for CD86 and CD80 ligands than the stimulatory receptor CD28. Consequently, CTLA-4 competes with CD28 for CD80 and CD86 (co-stimulating molecules) thereby serving as a checkpoint for T-cell response further leading to hyporesponsiveness or T-cell anergy (Linsley et al. 1994). Similarly, programmed death-1 (PD-1) has also been recognized as an immune checkpoint on T-cells or other immune cells. Along with its cognate ligands PD-L1 or PD-L2, PD-1 plays an important role in the process of peripheral tolerance to protect normal host tissue against self-reactive or specific T-cells by two mechanisms: blocking the escape of self-reactive T-cells into the periphery and promoting Treg development and function (Francisco et al. 2010; Fife and Pauken 2011). Thus, the immune checkpoint pathways play a crucial role in maintaining health by modulating harmony between protective T-cell response and T-cell tolerance.
Despite the fact that advancements in checkpoint-based immunotherapies for autoimmune diseases are relatively slow compared to that for cancer, this field has attracted a great deal of research interest. In both cases the aims for checkpoint-based immunotherapies are different where activation of T-cells is the prime aim in treating the cancer and chronic infections, whereas blocking the activation of self-specific or self-reactive T-cells is the prime goal in the treatment of autoimmune diseases (He et al. 2017). CTLA4-Ig (Abatacept) is an FDA-approved drug used to treat diseases like juvenile idiopathic arthritis and rheumatoid arthritis, and is currently being tested for other autoimmune diseases in several clinical studies. Abatacept is a soluble recombinant human fusion protein that is characterized by an extracellular domain of human CTLA-4 which is linked to a modified Fc domain of human IgG1.This agent binds to the co-stimulatory molecules B7–1/B7–2 present on APCs and mimics the action of the native CTLA-4. This results in the downregulation of autoreactive effector T-cell responses due to competitive inhibition of the crucial CD28:B7–1/B7–2 co-stimulatory signaling pathway(s) required for T-cell activation (Ruperto et al. 2008). The use of an Fc-chimeric version of PD-L1 in an in vitro model has demonstrated collapse of self-reactive T-cells on administration of a PD-1 agonist (McKinney et al. 2015). It is also demonstrated that the de novo generation of Tregs from naïve CD4 T-cells is amplified by PD-L1 (Francisco et al. 2009). These discoveries imply that it is possible to achieve dual benefits by utilizing the therapeutic capability of Tregs and concurrently reducing the augmentation proliferation and the role of activated self-reactive T-cells. Thus, it is important to understand and study the different molecular mechanisms of checkpoint-based immunotherapeutic agents particularly on Tregs and autoreactive activated T-cells in order to overcome the several autoimmune diseases by this novel approach. However, it is also critical to understand the fact that immunotherapies that repress activation or induce collapse of autoreactive T-cells can possibly trigger global immunosuppression. This may cause damaged immune function against infected or newly mutated cells or decreased immune control of malignancy and chronic infections. Hence, the use of checkpoint-based immunotherapies for autoimmune diseases remains challenging, where there is a strong need to improve specificity of these agents in order to minimize the immune-related adverse effects (irAE) (He et al. 2017).
4.6 Auto-Antigen Specific Immunotherapies for Autoimmune Diseases
Antigen specificity is considered as a fundamental mechanism of adaptive immunity. An alternate appealing approach to avoid global immune-suppression that can affect overall control of the immune system during the treatment of autoimmune diseases by immunotherapy is believed to be auto-antigen specific immunotherapies (ASIs). Hypothetically, minimal damage would be caused to the overall defensive immunity against foreign antigens acquired from microbial pathogens and cancer cells by restricting the induction of T-cell exhaustion only to the activated autoreactive (autoantigen-specific) T-cells that have escaped thymic deletion (He et al. 2017; Bluestone and Bour-Jordan 2012). It is a known fact that T-cell remains anergic (unresponsive) to the resultant antigenic challenges if it receives only antigen-specific stimulation through its TCR without the subsequent stimulation signal via its co-stimulating receptor (Chen and Flies 2013) .In concurrence with this idea, ASI has been investigated in mouse models and has been reported to reverse or prevent autoimmune diseases, thus demonstrating that inducing tolerance to a finite number of autoantigens or epitopes is adequate to elicit therapeutic benefits (Macleod and Anderton 2015). Thus, the goal of ongoing research in immune tolerance is the development of autoantigen-specific immunotherapeutic treatments such as ASI that allow for the specific blockade of the harmful effects of self-reactive immune-cell function while retaining the ability of the immune system to clear non-self antigens (Miller et al. 2007).
Antigen-specific tolerance can be induced by introducing an antigen under tolerogenic conditions rather than immunogenic conditions. In reality, antigen introduced orally or in soluble form appears to decrease, and not potentiate, subsequent immune response to the antigen. Thus, antigen-specific tolerance forms the basis for the use of allergen extract-based immunotherapy to treat allergies, and has been suggested as a potential means to treat autoimmune diseases (Smilek et al. 2014). Although ASI for autoimmune disease has the potential to control the disease much like allergen-specific immunotherapy, there are basic differences between both, including that allergic diseases consist of helper T-cell; Th2 dominant responses, whereas autoimmune diseases consist of Th1and Th17 dominant responses. If we understand the pathophysiology and identify the autoantigens involved in particular autoimmune diseases, it is possible to manipulate autoantigen-related pathways to induce immune tolerance against self-antigens. Based on this concept, several considerable efforts have been made to use ASI approach to modify the immune response in autoimmune diseases. Several studies in animal models that stimulate chronic inflammatory conditions have found that controlled administration of autoantigens can provide protection from autoimmune disease (Hirsch and Ponda 2014). Table 4.1 summarizes several ASI studies reported for the treatment of different autoimmune diseases.
From Table 4.1, it is clear that T1D is one of the most researched autoimmune diseases due to the availability of well-defined autoantigens and NOD mouse models. Although ASI for T1D has shown promising results in animal models and Phase I trials, few have shown efficacy in Phase II studies, raising concern that ASI for T1D therapy may not be a viable option. In the case of MS, some animal studies of EAE reported limited efficacy of oral/nasal administration of soluble myelin peptides in prevention of EAE but not in treatment of EAE after onset. Unfortunately, human clinical trials with oral bovine MBP have not been successful, and the oral route appears limited in inducing tolerance in ongoing disease. ASIs for RA have been limited by the lack of systematic knowledge of the pathogenesis of autoimmunity; whereas more studies are necessary to study the putative role of ASI for celiac disease, SLE, and other autoimmune diseases (Hirsch and Ponda 2014).
4.7 Anti-Cytokine (Anti-IL-1, Anti-IL-6, Anti-TNF Agents) Therapy for Autoimmune Diseases
During the development of the normal immune response, cytokines not only regulate a broad range of physiological processes but are also involved in the pathogenesis of autoimmune diseases. Autoimmune pathogenesis can be triggered when immune system cells recognize self tissue as foreign and the balance between pro- and anti-inflammatory cytokines is disturbed. Thus, anti-cytokine treatment alone and/or in combination with varied classes of immune suppressive molecules is highly effective, where some cytokines have been successfully identified as potential targets for the therapy of inflammatory/autoimmune diseases. Many anti-cytokine therapeutics are currently being used clinically, and many biologicals are in the pipeline (Astrakhantseva et al. 2014). There are three main categories of anti-cytokine agents which are popular for the treatment of autoimmune diseases: anti-interleukin 1 (IL-1), anti-interleukin 6 (IL-6), and anti-tumor necrosis factor (TNF) agents.
In 1975, TNF-α was found to be a specific product of macrophages and lymphocytes that induced breakdown of specific types of cells which also include tumor cells (Carswell et al. 1975). TNF-α is present on cell surfaces of lymphocytes and macrophages as a transmembrane protein. Cleavage of this protein leads to release of soluble TNFα. There are two TNF receptors that regulate the function of this mediator—TNFR1 and TNFR2. The TNFR1 receptor is membrane bound and upon stimulation by TNF-α releases other cytokines such as IL-2 and interferon (IFN), while the soluble TNFR2 receptor is present in the extracellular milieu where it serves to deactivate soluble TNF and blunts its inflammatory activity (Ostrov 2015). Various clinical trials of TNF inhibitors have revealed that it is possible to abrogate immune system activation, control inflammation, mitigate damage to joints, and sometimes cause stable remission in patients after discontinuing anti-TNF therapy merely by inhibiting a single cytokine (Huang et al. 2012; Verazza et al. 2013; Regueiro et al. 2014). Infliximab is the first TNF inhibitor that was found to be effective for patients with RA and Crohn’s disease (unresponsive to conventional therapy). Later, it was also demonstrated to be efficacious in the treatment of psoriasis and ankylosing spondyloarthritis. Currently, various autoimmune diseases are effectively being treated with the use of TNF inhibitors, and five TNF inhibitors are approved in the majority of developed countries (Astrakhantseva et al. 2014).
IL-1, the first identified cytokine, was called the “endogenous pyrogen” because of its main action of inducing fever. IL-1α and IL-1β are the active products of this cytokine. Inactive IL-1β is cleaved to the active form by the inflammasome complex leading to the signs of inflammation (Ostrov 2015). IL-1 cytokines are a key factor in regulating the immune response and developing inflammation by controlling the expression of numerous effector proteins like chemokines, cytoplasmic metalloproteinases, cytokines, etc. (Dinarello 1996). Dysregulated IL-1α/β synthesis/secretion may result in grave pathologies. Upregulated IL-1α/β due to activation of its synthesis/secretion by triggering inflammasomes is generally responsible for many “classic” chronic inflammatory diseases. Several chronic inflammatory diseases including cryopyrin-associated periodic syndromes (CAPS), gout, multiple sclerosis, hypertension, type-2 diabetes, etc., are associated particularly with the increased level or production of IL-1β. These chronic inflammatory diseases are actively treated by IL-1 inhibitors like anakinra, rilonacept, and canakinumab which inhibit signal transduction pathways via IL-1/IL-1receptor (IL-1R) and thus crosstalk with the cycle of inflammation (Astrakhantseva et al. 2014).
Another key cytokine which along with IL-1 and TNF contributes to inflammation in autoimmune diseases is IL-6. It stimulates B-cell antibody production, elevates inflammatory serum markers (especially C-reactive protein), and promotes Th17 cell maturation (Ostrov 2015). Dimerization of gp130 is initiated by the receptor binding of IL-6 which leads to the activation of JAK tyrosine kinases. Activated JAKs further phosphorylate and activate STAT transcription factors, e.g. STAT3 for IL-6 receptor; hence, dysregulation of this cytokine network may result in autoimmune diseases, chronic and acute inflammations, and neoplastic disorders (Astrakhantseva et al. 2014; Heinrich et al. 1998). The uncontrolled production of IL-6 may cause various chronic inflammatory and autoimmune diseases by shifting the balance to the side of Th17/Th1 side with Treg reduction (Kimura and Kishimoto 2010). Tocilizumab, an inhibitor of IL-6, was the initial molecule clinically approved in its class. It alters common IL-6-receptor (IL-6R) complex functioning, and inhibits downstream activation of adhesion molecules, osteoclasts, and maturation of both B- and T-cells (Rosman et al. 2013). This agent is approved by the FDA to treat RA, adult-onset Still’s disease (AOSD), systemic juvenile idiopathic arthritis (JIA), and polyarticular JIA. Tocilizumab has also undergone recent promising trials in SLE and Crohn’s Disease (CrD) (Ostrov 2015). The clinical success of tocilizumab led to the development of other inhibitors of IL-6 such as sirukumab, sarilumab, olokizumab, and clazakizumab, which are now in the second phase of clinical trial (Tanaka and Mola 2014). Table 4.2 summarizes the recent anti-cytokine immunotherapeutics with their characteristic features and therapeutic applications. In summary, besides the few limitations of anti-cytokine immunotherapy due to its ability to affect basic protective bodily functions through specific cytokines, its use in the clinical setting for autoimmune diseases and chronic inflammatory diseases is, indeed, revolutionary. Based on enhanced understanding of the molecular mechanisms of cytokine-associated pathologies, it is already being actively used in several countries and will most certainly become a trail-blazing trend in clinical medicine in the future (Astrakhantseva et al. 2014).
4.8 Anti-T-Cell Therapy for Autoimmune Diseases
Emerging knowledge from the current developments in the field of immunotherapy has revealed that peripheral tolerance mechanisms that fail in autoimmunity are implicated in progressive malignancies and chronic infections. Thus, pathways targeted for therapeutic intervention in autoimmune diseases can be modulated in the opposite sense in malignancy and infectious disease (Bucktrout et al. 2018). Major therapeutic strategies of anti-T-cell therapy for autoimmune diseases are immunomodulation of T-cell co-stimulation, migration, and inflammation. The rationale behind the development of such therapies is that such immunotherapeutics could selectively target pathogenic T-cells during autoimmune conditions. It has been observed that CD28, a co-stimulatory molecule, expresses on T-cells; and that interaction of CD28 with B7–1 or B7–2 is necessary for T-cell activation as well as effector function. Thus, inhibiting CD28/B7 interactions in the TCR signaling axis may lead to tolerance resulting from deletion of T-cells and/or anergy, which is important to re-establish tolerance in autoimmune diseases (Bluestone and Bour-Jordan 2019). In vivo studies showed that abrogation of CD28 signaling by means of a fusion protein of CTLA4Ig was efficacious in ameliorating many autoimmune diseases such as MS or SLE (Scalapino and Daikh 2008). Two fusion proteins (CTLA4Ig) composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4, viz., Abatacept and Belatacept (the higher-affinity Belatacept which is a second-generation variant) demonstrated more than 50% response rate in patients with psoriasis and RA who were refractory to anti-TNF-α therapy; these are approved by FDA for RA/JIA (Genovese et al. 2005). However, abatacept could not reduce disease flares during Phase II studies on SLE patients treated with oral corticosteroids, and was found ineffective in a Phase III trial of CrD (Merrill et al. 2010). The lack of response to abatacept in patients with CrD may be due to limited co-stimulatory activity by intestinal T-cells which do not express CD28 (Mayer et al. 2012). In a recent multi-center trial in newly diagnosed T1D patients, treatment with abatacept for 2 years was well tolerated and delayed the reduction in B-cell function compared with placebo (Orban et al. 2011). Many clinical studies of abatacept or belatacept are currently ongoing in SLE, MS, or T1D. Current therapy with CTLA4Ig was not found to lead to extensive immunosuppression or augmented infection rates, which is clearly beneficial in the therapy of autoimmune disease (Bluestone and Bour-Jordan 2019). Alefacept is a fusion protein of LFA-3-Ig that inhibits the interaction of lymphocyte function-associated antigen 3 (LFA-3/CD58) on the APCs with CD2, a co-stimulatory molecule on T-cells. It was reported to be efficacious in decreasing lesions in a psoriasis Phase III trial and is currently FDA-approved for psoriasis (Sugiyama et al. 2008). It has been reported that interactions between CD154 and CD40, the former on T-cells and the latter on APCs, are critical for stimulating autoreactive T-cells, activating APCs and producing autoantibodies; hence therapeutic abrogation of this pathway appeared promising in the 1990s. Unfortunately, clinical studies of anti-CD154 monoclonal antibodies were initiated in many autoimmune diseases such as SLE, CrD, MS, and psoriasis, but had to be discontinued due to occurrence of many thromboembolic events (Bluestone and Bour-Jordan 2019).
It is a well-known fact that key factors for the inducing or maintaining tolerance include T-cell trafficking and lymph node occupancy. Hence, immunotherapies which target T-cell migration in autoimmune disease may be used in combination therapy during immunosuppression to enable homing to lymph nodes of autoreactive T-cells and their tolerization (Bluestone and Bour-Jordan 2019; Ochando et al. 2005). Based on this theory, two most successful drugs developed for cell trafficking blockade are anti-integrin mAbsnatalizumab and efalizumab. These drugs are indicated in relapsing-remitting multiple sclerosis (RRMS), CrD, and psoriasis (Dubertret et al. 2006; Derfuss et al. 2013).. Natalizumab, an FDA-approved mAb for CrDor RRMS, for patients suffering from severe disease or disease which is non-responsive to other standard-of-care, needs to carry an additional label warning. Further, efalizumab has been voluntarily withdrawn by the manufacturer due to the association of progressive multifocal leukoencephalopathy (PML) cases with the treatment (Hartung 2009). Another drug fingolimod capable of regulating T-cell trafficking by crosstalk with members of the sphingosine pathway was also found to improve the rate of relapse and progression to disability within 1–2 years in a Phase III clinical trial of RRMS patients and thereby turned out to become the first oral therapeutic approved by the FDA for MS (Kappos et al. 2010; Cohen et al. 2010). Due to the adverse effects associated with fingolimod therapy, second-generation molecules targeting the sphingosine signaling pathway are in development with potentially decreased side effects, and clinical trials are in progress for many autoimmune diseases (Bluestone and Bour-Jordan 2019). Along with these T-cell immunomodulation strategies, immunotherapies targeting proinflammatory cytokines (discussed in the previous section) or other inflammatory mediators in autoimmune diseases are also found to be useful, not just for improvement in clinical parameters but also for their ability to restore tolerance.
4.9 Anti-B-Cell Therapy for Autoimmune Diseases
The B-cell humoral response leading to production of autoantibodies and immune complexes contributes to manifestations of autoimmune diseases such as SLE and Sjogren’s syndrome. The B-cell dysfunction contributes to the development of autoimmune phenomena via anomalies in B-cell’s mechanisms such as antigen presentation, cytokine release, and T-cell activation (Ostrov 2015). From the last 10–15 years, B-cells are the recognized therapeutic targets for the treatment of autoimmune diseases. Presently, several promising and very efficient drugs specifically targeting plasma cells or B-cells are either in clinical use or under development for the treatment of several autoimmune diseases. These B-cell-directed therapies have proven to be therapeutically effective not only in classic B-cell/autoantibody-driven disorders, such as antibody/immune-complex-mediated SLE, autoimmune blistering skin diseases, or myasthenia gravis, but also in diseases that are believed to be mainly driven by T-cells, most importantly MS or RA (Hofmann et al. 2018). B-cells were recognized for their function as immune response enhancers in autoimmunity, as a result of their ability to generate autoantibody-producing plasma cells, and elicit CD4+T-cell responses by antigen presentation. Such B-cells are typically classified as effector B-cells. Recently, studies indicated a potential role(s) of B-cells as negative sensors of immune response in autoimmunity, implicating interleukin 10 (IL-10) regulatory B-cell compartment (Breg). Thus, the abrogation of autoreactive effector B-cells in consonance with enhancement of autoantigen-driven Bregs, with immune surveillance maintenance, may be a key strategy to target B-cells. Anti-B-cell immunotherapies employ drugs directed against B-cell surface markers such as CD20/CD22, activating factors such as BAFF/TACI, and cytokines such as IL-6/TNFα/IFNα to target these B-cells (Musette and Bouaziz 2018). Table 4.3 summarizes the recent strategies to target B-cells with their drugs and implications in autoimmune diseases.
From the literature, it is clear that a great advancement has been made in decreasing resident and circulating B-cells in inflamed tissues or secondary lymphoid organs. The future of immunotherapy may require specific targeting, particularly of B-cell pathogenic effector functions, and augmentation of their regulatory role(s) without altering B-cell-dependent immune surveillance. Indeed, better patient management will be possible with better targeted therapeutics against specific B-cell populations and their functions (Musette and Bouaziz 2018).
4.10 Current Immunotherapeutics in Clinical Trials for Autoimmune Diseases
Several clinical trials are being performed on immunotherapeutics for autoimmune diseases as seen in Table 4.4. The majority of these molecules are being tested for safety and efficacy in psoriasis and rheumatoid arthritis. In both these diseases, one notes a larger proportion of immunotherapeutics in advanced clinical testing including Phases II and III. There is also considerable work that is ongoing with several immunotherapeutics in clinical trials for SLE, many of which are in Phase I or II. Interestingly, there are fewer immunotherapeutics in clinical trials for IBD, Crohn’s disease, and MS; however, the few that are being investigated are mostly in Phase III. As seen in Table 4.4, there are a huge number of immunotherapeutics in clinical trials for various autoimmune diseases, and the number is likely to increase in the near future given the promise of immunotherapy in these diseases.
4.11 Financial Toxicity of Immunotherapies in Autoimmune Diseases
In recent years, the cost of immunotherapies in general and indeed for autoimmune diseases is reaching great proportions which brings into picture the financial burden which the patients and their families suffer from in different parts of the world despite having access to health insurance (Nipp et al. 2018; Zaprutko et al. 2017). The spectrum from diagnosis to treatment and post treatment care involves huge investments, financial as well as emotional, by the patients and their families who are afflicted by autoimmune diseases like CrD, inflammatory bowel syndrome (IBD), Grave’s disease, MS, psoriasis, RA, Sjogren’s syndrome, SLE, etc. (Lerner et al. 2015).
Inflammatory Bowel Syndrome, Crohn’s Disease
Zheng et al. and Ylisaukko-Oja et al. discussed in their studies how along with cost of biologics, the secondary costs for outpatient visits, hospitalization, telephone consultation, laboratory visit, surgery, imaging, endoscopy added to the total cost of the treatments of inflammatory bowel syndrome (IBD) (Zheng et al. 2017; Ylisaukko-Oja et al. 2019). According to Berns et al., in previous years a patient with CrD was burdened with surgical intervention and hospitalization charges only but with modern anti-TNF-α biologic era the treatment itself accounted for 64% of the total cost, which was around $22,663 for infliximab in the United States. However such burden can be brought under control in future by the use of biosimilars which have equivalent efficacy and safety profile as soon as the patent for branded biologics expire, which will no doubt have a positive economic impact with immense cost savings for the patients (Berns and Hommes 2016). When Severs et al. through COIN study compared the cost burden of biologic drugs and biosimilars it was found that in a Dutch IBD population of 85,400 patients [equaling 507 patients per 100,000 inhabitants, 55% UC and 45% CD patients], there was a cost saving of €493 million with biosimilars which is almost a reduction of 28% in the total healthcare costs which also covered the costs of IBD-specific hospitalizations, outpatient clinic visits, and surgeries of the inhabitants (Severs et al. 2016).
Multiple Sclerosis
Hartung et al. reported that the first generation of disease modifying therapies (DMTs) for MS in 1993 costs the patient $8000 to $11,000, but with the entry of new DMTs the prices increased up to $60,000 in the year 2013 because they are prescription drugs which were affected by medical inflation in the United States (Hartung et al. 2015). Hartung et al. and Chen et al. found out that this amount went up to $70,000 in the United states in the year 2017, which was due to an increase in the costs of patient care facilities (Chen et al. 2017; Hartung 2017). Similarly, the annual costs for MS in European countries like Spain and France were around €30,050 and €38,100, respectively, on a per patient basis in the year 2017 (Fernández et al. 2017; Kobelt et al. 2017).
Psoriasis
The economic burden associated with psoriasis is significant and it increases even further as the disease progresses from moderate to severe (Al Sawah et al. 2017; Augustin et al. 2017). The United States in the year 2013 estimated an overall expense of $11,498 was paid by an individual patient of psoriasis throughout his treatment (Brezinski et al. 2015; Vanderpuye-Orgle et al. 2015). Meanwhile in European countries like the United Kingdom, France, Germany, Spain, and Italy, the cost of the treatment was in the range of US$2077–13,132 (Augustin et al. 2017; Burgos-Pol et al. 2016).
Rheumatoid Arthritis
RA, a systemic autoimmune disorder accounts for economic burden in the range of €2.0 billion per year in European nations which included direct costs of the biologics and indirect costs of the various services and maintenance for the early rapidly progressing RA (ERPRA) patients (Mennini et al. 2017; Cross et al. 2014). A similar approach of using biosimilars of these biologics will result in decreased economic burden in the future (Gulácsi et al. 2015).
Systemic Lupus Erythematosus
SLE is a multisystem autoimmune disease that could potentially lead to serious organ complications and even death with its incidence being as low as 0.3–31.5 cases per 100,000 individuals every year (Carter et al. 2016; Sebastiani et al. 2016). The annual cost for hospitalization was US$51,808.41 per patient in Rochester city of New York state for an approximate stay of 8.5 days in the hospital (Anandarajah et al. 2017). Meacock et al. concluded that in a randomized population in the United States, the mean annual treatment cost was in the range of US$2239–$35,540 until the year 2010 (Meacock et al. 2013).
4.12 Conclusion and Future Perspectives
There has been great progress and renewed interest in immunotherapies for autoimmune diseases. As discussed, various modalities ranging from immune checkpoint blockade to anti-T-cell therapy or anti-B-cell therapy, amongst others are in current use. This has seen the emergence of very many novel immunotherapies which we have delineated earlier. Of interest, there are a sizeable number of immunotherapies for autoimmune diseases in early and advanced stages of clinical trials and recent trends indicate that their number is only going to increase. Although this is laudable to provide access to better care to suffering patients, one needs to also balance the financial toxicity of these immunotherapies which can oftentimes defeat the very purpose of providing healthcare to those who need it most. It is recommended that all stakeholders from discovery scientists to clinicians to health management organizations and insurance providers as also lay members of the public be brought on the same page to appreciate all these “facets” of immunotherapies to make it a successful and go-to healthcare therapy for autoimmune diseases in the future that will benefit a greater proportion of patients.
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Mali, A., Sawant, A., Mahadik, A., Nair, S. (2021). Immunotherapy for Autoimmune Diseases. In: Sawarkar, S.P., Nikam, V.S., Syed, S. (eds) Immunotherapy – A Novel Facet of Modern Therapeutics. Springer, Singapore. https://doi.org/10.1007/978-981-15-9038-2_4
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