Immune Rebalancing: The Future of Immunosuppression

Netherlands

Chapter 1

Pharmacological Strategies Using Biologics as Immunomodulatory Agents

Diana Boraschi¹ and Giselle Penton-Rol²,    ¹Institute of Protein Biochemistry of the National Research Council, Napoli, Italy,    ²Center for Genetic Engineering and Biotechnology (CIGB), Habana, Cuba

Abstract

Immunosuppressive approaches have been used successfully for over a century for the therapy of diseases in which an anomalous immune activation is part of the pathology, such as autoimmune diseases and acute and chronic inflammatory and degenerative diseases. General anti-inflammatory and immunosuppressive drugs, starting with aspirin and corticosteroids, have been used and still are used with good clinical efficacy but significant collateral effects. In the last decades, more targeted approaches have aimed at blocking specific molecules of the pathological immune response, in an attempt to increase efficacy while decreasing side effects. Having realized that immune and inflammatory activities are involved in practically all diseases, including cancer, a more recent approach foresees the rebalancing of the anomalous responses, so as to eliminate the pathology-related alterations whilst at the same time maintaining the protective efficacy of both innate and adaptive immunity. In this review, we will go through the evolution of immunosuppressive treatments, with special emphasis on the use of biologics.

Keywords

Immunosuppression; immunomodulation; therapy; prevention; biologics

1.1 Introduction

Immunosuppression has been used by physicians for many decades for blocking the unwanted activities of the immune system. In the last century, the history of therapeutic immunosuppression has paralleled the history of immunology as studies on transplantation immunity have allowed us to gain a deeper understanding of the rules of activation and regulation of adaptive immunity.¹ The discovery of the major histocompatibility complex (MHC) dates back to 1967,² and since then we have understood the rules of antigen presentation and cross-presentation, cognate interaction, activation of the different T cell subsets, and antibody production. MHC typing has allowed us to better match organ donors with recipients, but has not avoided the need for immunosuppressive treatments to the recipient. Depending on the type of transplant (bone marrow or solid organs), immunosuppressive regimens could include whole body irradiation and immunosuppressive drugs, such as cytostatic molecules (azathioprine was first used as an immunosuppressive treatment in a kidney transplant in 1959), antimetabolites, corticosteroids, and antibodies against leukocytes and their products. The rough concept is that during an immune response against the allotransplant, the specific immune cells start proliferating and are metabolically active, thus they are better targets for drugs inhibiting metabolism and proliferation. The drawback is that several other cell types in the body are metabolically active and proliferating, for instance the epithelial cells of respiratory and gastrointestinal mucosae, hair follicles, and several others, including immune cells when combating an infection or a disease. Thus, life-long generalized immunosuppression may allow the allotransplant to survive in the host, but it can cause side effects that can become severe and life-threatening.

Immunosuppressive strategies are used not only for transplanted patients but also, more widely, for treating asthma and allergies, and autoimmune and chronic inflammatory and degenerative diseases, that is, pathologies due to the deranged reaction of the immune system either to innocuous agents (eg, pollens), or to endogenous molecules and structures (autoreactivity), including cell membrane components, nuclei, DNA, and myelin. Most of these diseases have, in addition to the component of anomalous adaptive immune reactivity (for instance the production of autoantibodies), a strong inflammatory component. This includes all the mechanisms of innate immunity, with activation of leucocytes, production of inflammatory factors, and consequent tissue damage/destruction. The persistent inflammatory activation can also bring about the anomalous feed-back activation of repair mechanisms that may lead to nonfunctional neotissue apposition and pathological fibrosis, as in the case of systemic sclerosis. Immunosuppressive and anti-inflammatory treatments are in the vast majority of cases life-long treatments, since the immunosuppressive strategies basically address the damage-inducing immune activation caused by the disease, rather than the cause of the disease.

A summary of the classical immunosuppressive treatments that are being used is provided in Table 1.1.

Table 1.1

Classical Immunosuppressive Regimens

1.2 From Nonspecific to Targeted Immunosuppression

Immunosuppressive approaches have experienced a wide development in more recent times, with the advent of two important technological advancements, that is, the recombinant DNA and the monoclonal antibody technologies. The use of recombinant proteins and of monospecific antibodies has allowed the physician to direct the immunosuppressive drug to a single molecule/mechanism involved in the disease, in the attempt to achieve better efficacy and lower side effects.

Anticytokine antibodies and cytokine inhibitors are among the most important treatments for autoimmune/chronic inflammatory diseases.

In the list of the best-selling drugs in 2014 (Table 1.2), it is impressive that eight of the first 25 are immunosuppressive drugs, and of these five are biologics. This underlines the still open medical need for more efficient immunosuppressive treatments, and the current success of biologics.

Table 1.2

The 25 Best-selling Drugs in 2014

In bold-italic: immunosuppressive/anti-inflammatory biologics; in italic: non-biologic immunosuppressive/anti-inflammatory drugs; in bold: biologics not aiming at immune suppression.

mAb: monoclonal antibody; TNFα: tumor necrosis factor α; RA: rheumatoid arthritis; JIA: juvenile idiopathic arthritis; HCV: hepatitis C virus; CD20: cluster of differentiation 20 (surface molecule expressed by B cells); HL: non-Hodgkin’s lymphoma; CLL: chronic lymphocytic leukemia; VEGF-A: vascular endothelial growth factor A; HER2 (human epidermal growth factor receptor 2); ADCC: antibody-dependent cellular cytotoxicity; COPD: chronic obstructive pulmonary disease; G-CSF: granulocyte colony stimulating factor; MS: multiple sclerosis; COX-2: cyclooxygenase 2.

Source: Information taken from Genetic Engineering and Biotechnology News, February 23, 2015.

Three anti-TNFα biologics are within the first five best-selling drugs: Humira (a human mAb recognizing the inflammatory cytokine TNFα) is the first in the list, with Remicade (humanized mAb) and Enbrel (chimeric receptor) at the third and fifth position, respectively. The anti-TNF treatments, usually after or in combination with DMARDs (disease modifying antirheumatic drugs) are active in autoimmune and chronic inflammatory diseases, in particular rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondilitis, Crohn’s disease, and ulcerative colitis.³ Another very successful immunosuppressive biological drug is Rituxan, a mouse/human chimeric mAb against CD20, an antigen preferentially expressed by activated B cells. Rituxan is used in a series of different diseases in which inhibition of B cell responses is beneficial (eg, autoimmune diseases, transplant rejection) and also for killing tumor cells in B cell lymphomas and leukemias.

The cost of therapies with biologics is significant. For instance, one-year treatment with anti-TNF therapy costs about US$20,000 for a single patient. The cost of Sovaldi (which however is not a biologic drug) peaks at US$84,000 for the full 12-week treatment course. These costs are excessive and necessarily limit the access to the cure. Also, a recent study has highlighted the fact that the success of many of these drugs is partial, with about 25% of treated US patients actually benefiting from anti-TNF therapy, while for other drugs the success is even lower (Table 1.2).⁴ Thus, given the costs, predicting response and patients’ stratification are a priority for the public health services. On the other hand, given the partial success of these treatments, it is obvious that new more effective approaches are required.⁵

1.3 From Immunosuppression to Immune Rebalancing

The range of applications of immunosuppressive therapies has become increasingly wider as the mechanisms of disease initiation and progression are being clarified. Thus, it is now obvious that most diseases are based on anomalous immune regulation. In fact, it is known that the immune system needs to establish and maintain an effective balance between reaction to foreign possibly dangerous agents (such as invading microorganisms) and unresponsiveness to harmless agents (eg, the microbiota) and self-molecules. Disruption of the balance between response and tolerance, and the consequent immune dysregulation can cause pathologies such as cancer (in which inflammation and immunosuppression play an important role in allowing tumor growth), metabolic diseases (obesity, diabetes), degenerative diseases including Alzheimer, Parkinson, Amyotrophic Lateral Sclerosis, respiratory and cardiovascular diseases, in addition to the typical allergic and autoimmune diseases.

The new biologics and the single-target small molecules that have been developed in the last decades have allowed the design of better treatment protocols for some specific diseases (see for instance the case of the anti-CD20 mAb for B cell lymphomas and leukemias), but have also underlined the complexity of many diseases that in most cases cannot be treated by inhibiting a single target. Also, inhibition of single specific targets has given us a glimpse of the importance of such targets in the organism’s homeostasis. This is the case of anti-TNF therapies, which have revealed to the medical community the importance of TNFα for protection against Mycobacterium tuberculosis. In fact, treated patients are more prone to get infected or to reactivate tuberculosis (if they are carriers). This limits the application of the anti-TNF therapy to people that are tuberculin negative, to limit the risk of reactivation.

Many other mAbs and biologics have been/are being developed for targeting immune cells, in particular in cancer therapy. Antibodies that disrupt the PD-1 receptor on activated T cells (pembrolizuman and nivolumab) essentially block their apoptosis thereby allowing immune recognition and destruction of the cancer cells. Ipilimumab, an antibody against CD152 (CTLA4, an inhibitory molecule of T cells), blocks the immunosuppression mediated by it and allows more efficient T cell activation and consequently a better response against cancer. These Immune Checkpoint Inhibitors (ICI) are the most promising new anti-cancer approach. Cancer disrupts the normal regulation of immune responses, by inhibiting most of them to increase its chances of successful growth, thus the new treatments that are being devised intend to reattain the normal defensive immune functions by eliminating the blocks that do not allow full antitumor activation. As an example, it is known that pathological events induce the so-called emergency hematopoiesis for increasing the number of immune cells, and that tumors can reprogram this process giving rise to immature immunosuppressive myeloid cells.⁶ The identification of the switch molecule used by tumors for reprogramming such myelopoiesis, and the efficacy of its blockade in inhibiting tumor growth, open the way to a new immune rebalancing approach in anticancer therapy.⁷

Although biologics represent a major advance in the treatment of several diseases, notably rheumatoid arthritis, inflammatory bowel disease, and psoriasis, effective therapy for other autoimmune conditions, such as type 1 diabetes, remain elusive and will likely require targeting multiple immune components. Approaches of ex vivo immune cell education or combination therapies with different biologics and cells are being actively investigated, in the attempt to control autoimmune disease manifestations and restore the tolerant state.⁸

Restoration of tolerance is a medical issue of key importance that is gaining great attention. Knowledge of the role of regulatory T cells (Tregs) in the establishment and maintenance of immunological tolerance⁹,¹⁰ opens the possibility of targeting the Treg suppressive functions as an effective way of controlling immune responses, Thus, Treg modulation may become an important therapeutic opportunity for the treatment of a number of important diseases. The importance of achieving an accurate balance, when attempting to modulate immune responses, was shown in several studies. As an example, exploiting Treg activity in haploidentical hematopoietic cell transplantation (a potential therapeutic strategy for patients with hematological malignancies¹¹,¹²) would need a deeper understanding of how to modulate the T cell regulatory networks.¹³ Indeed, if T cells are included in the donor graft, this would cause graft-versus-host disease (GVHD), while T cell depletion would avoid GVHD and considerably increase the risk of severe infections and tumor relapse.

The US Food and Drug Administration (FDA) has approved several agents for modulating Treg activity in anticancer trials. Cyclophosphamide, fludarabine, anti-CTLA4 antibodies, and PD-1 blockers have had considerable success in circumventing Treg activity through different mechanisms of action and, in turn, in enhancing killer cell activity.¹⁴–¹⁸ Treg transfer is also a promising therapeutic option in controlling severe inflammatory diseases, as shown in experimental models of colitis.¹⁹ There are also indications that the immunosuppressive and anti-inflammatory effects of corticosteroids may in part be via Treg activation.²⁰,²¹

An important issue in the use of biologics for modulating immune responses is their immunogenicity, which could induce the host reaction and the production of antidrug antibodies (ADA) thereby hampering their efficacy. In the case of monoclonal or chimeric antibodies, ADA usually target foreign sequences that are not present in natural human antibodies. Replacement of foreign sequences with human sequences (humanization) is the most common approach for decreasing antibody immunogenicity. However, even fully human mAbs can be immunogenic. In such cases, the introduction of T regulatory epitopes can be adopted, so that the biologic drug would induce tolerance rather than immunity.²² The most recent document issued by FDA regarding the immunogenicity of biologics is the Draft Guidance for Industry Immunogenicity Assessment for Therapeutic Protein Products in August 2014.²³ The European Commission and EFPIA have started a Europe-wide project, in the context of the Innovative Medicine Initiative-Joint Undertaking (IMI-JU), to merge academic and industrial efforts in addressing the problem of immunization against biologics. The project ABIRISK (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk) puts together nine companies and 25 academic institutions with the aim of solving the problem of biologics’ immunogenicity to design new nonimmunogenic drugs, and also to generate tools for predicting the patients’ response to the biological drugs.²⁴

1.4 Conclusions

As detailed in this chapter, it is obvious that immune rebalancing is the future direction that immunosuppressive and immunotherapeutic strategies will take, with a particular focus on autoimmune, inflammatory, and degenerative diseases (such as rheumatoid arthritis, Crohn’s disease and inflammatory bowel disease, multiple sclerosis and neurodegenerative diseases, allergies) and cancer. The immune rebalancing strategy includes a series of approaches that need a concomitant harmonized development.

1. Precision medicine. Treatment should be tailored to the individual patient, like in the old concepts of Chinese traditional medicine, because there are no drugs that are good for everybody.⁵ From this perspective, systems medicine, which exploits omics technologies for profiling the patient and its reactivity, may help to establish new medical concepts. Also, new valuable information will come from a better understanding of the chimeric state of human beings, who encompass 10 times more bacterial cells than human cells. Modulating the microbiota hosted in our body provides a precious strategy for modulating our immune responses.²⁵

2. New drugs, new targets. Rediscovering natural products, both as a source of new molecules and as treatment procedures, could provide strategies of treatment that are more suited to precision medicine than the classical drugs.²⁶,²⁷ New targets that are common to practically all patients could come from the knowledge of innate immune mechanisms (that are practically unaltered in living organisms), and could include mononuclear phagocytes and their products (eg, IL-1).²⁸

3. New delivery approaches. A very promising technological advancement, ie, nanotechnology, has provided us with the possibility of using a practically endless array of novel carriers that can be built to form whatever kind of material, shape, size, surface characteristics, layers and tropism, we could wish.²⁹ Taking drugs specifically to their targets, without being eliminated by the body’s defense mechanisms and without unwanted interaction with bystander cells could indeed be achieved by nanomedicine.³⁰

Acknowledgments

DB is supported by the EU projects HUMUNITY (FP7-PEOPLE-INT-2012 GA n. 316383) and BioCoG (FP7-HEALTH-2013-INNOVATION-1 GA n. 602461), and the Cluster project Medintech of the Italian Ministry of Education, University and Research.

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