COPHAR-1435; NO. OF PAGES 3
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Immunomodulation: New insights for future treatments Stephen M Anderton and Simon Fillatreau Current Opinion in Pharmacology 2015, 23:xx–yy
http://dx.doi.org/10.1016/j.coph.2015.06.005 1471-4892/Published by Elsevier Ltd.
Stephen M Anderton
University of Edinburgh, MRC Centre for Inflammation Research, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK e-mail: [email protected] Steve Anderton is Professor of Therapeutic Immunology at the University of Edinburgh. He leads on the theme of ‘‘Immune Modulation and Regulation of Inflammation’’ at the Medical Research Council Centre for Inflammation Research. His main research focus is on the signals that lead to activation or tolerance in T cells that cause autoimmune and allergic disease.
Simon Fillatreau
Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany e-mail: [email protected] Simon Fillatreau studied biology at Ecole Normale Superieure de la rue d’Ulm, in Paris, and did his PhD in the laboratory of Prof. David Gray, at the University of Edinburgh, UK. Since 2003, he is group leader at the Deutsches Rheuma-Forschungszentrum, a Leibniz Institute in Berlin, Germany. His group is interested in the processes regulating immune responses to pathogens and self-antigens. www.sciencedirect.com
Chronic inflammatory diseases including autoimmune and allergic disorders cause major disability, and their incidence is dramatically increasing. Current predictions from the World Health Organization estimate that 50% of the world population will be affected by at least one allergic disease by 2050. Whilst we remain without curative treatments for these diseases, recent years have seen a considerable increase in immunotherapeutic options that are available. These include biologics targeting effector molecules or defined sub-populations of immune cells that cause inflammatory pathology, as well as small molecule inhibitors targeting intracellular signaling molecules with key role in these pathologies. In addition, novel approaches based on a better understanding of immune regulation mechanisms are emerging, which might eventually deliver more-specific approaches for treating these chronic inflammatory diseases. This issue aims to provide an overview of these various types of treatments for immune modulation, from those already applied in the clinic, to those that are still in development and may deliver novel forms of immunotherapies in the future. Since TNF-a-blockade provided a proof-of-principle that disrupting a single molecule in a key inflammatory pathway could result in a marked amelioration of chronic inflammatory disease, targeted immunotherapy through use of biologic drugs has evolved into a multi-$billion industry [1]. In cancer, where immunomodulation needs to enhance rather than degrade immunity, the advent of inhibitory checkpoint release using biologic agents also promises to be transformative [2]. Besides the growing number of possible targets for such approaches, technological advances, such as the development of nanobodies, intrabodies and designed ankyrin repeat proteins (DARPins) are providing new ways to use this class of drugs, which promise an even broader application [3–5]. An optimal use of these therapeutic approaches requires that the patients who would benefit from their application can be robustly identified. Whilst this important issue is true for various biologics-disease combinations, it can be exemplified in the use of TNF-a-blockers in Crohn’s disease. Here, Markus Neurath describes how recent advances in clinical molecular imaging can provide a critical stepchange in delivering these blockers in a personalized manner by identifying those patients with the most pronounced TNF-a signature as the most likely to benefit from these treatments. It is likely that similar imaging-based approaches should be applicable to other molecular targets in diseases affecting tissues at body surfaces, including other gastrointestinal disorders as well as inflammatory diseases of the lung and genitourinary tract. Beyond targeting key inflammatory cytokines, biologics are also used to target specific immune cell types. Such approaches can lead to an elimination of most Current Opinion in Pharmacology 2015, 23:1–3
Please cite this article in press as: Anderton SM, Fillatreau S: Editorial overview: Immunomodulation: New insights for future treatments, Curr Opin Pharmacol (2015), http://dx.doi.org/10.1016/ j.coph.2015.06.005
COPHAR-1435; NO. OF PAGES 3
2 Immunomodulation
of the cells within an entire lymphocyte subset, such as B cells after treatment with rituximab. A major drawback of such an approach, as well as of those that block specific homing molecules, is that they lead to a global impairment in immunity, including protective immunity against potentially fatal infectious agents, and they usually only eliminate drivers of the disease without restoring immune-regulatory mechanisms to a sufficient degree to provide a stable restoration of a healthy immune system, therefore requiring prolonged treatment, and consequently persistent immune suppression. In this issue, Lucienne Chatenoud discusses these various strategies, taking into accounts the risk-benefit considerations that are required with the use of biologics, and introduces the possibility of using a distinct class of biologic agents that can achieve a restoration of immune tolerance. Despite the advent of biologics, which revolutionized the treatment of chronic inflammatory disorders, the development of new pharmacological inhibitors remains a highly promising avenue to obtain novel drugs for these diseases. Resorting to small molecule drugs may in fact be a necessary alternative. Together, the increasing prevalence of chronic inflammatory disorders, the fact that currently available drugs must be applied life-long, and the cost of biologics, mean that biologic drugs might ultimately place too great a financial strain on health care providers; a question that is important to bear in mind. More affordable small molecules therefore remain an important alternative, particularly if they can match the efficacy seen with biologics. An added advantage of such an approach might be oral rather than parenteral delivery. Janus kinases (Jaks) are essential signaling intermediates downstream of type I and type II cytokine receptors. The development of a series of Jak inhibitors (Jakinibs) has recently paved the way to the application of kinase inhibitors in immunomodulation of autoimmune disease [6]. Another family of kinases, the PI3 kinases, plays major roles in immune cell functions and Klaus Okkenhaug et al. discuss the prospects of targeting these therapeutically. Despite the advantages that might come from the use of small molecule modulation of immune cell signaling pathways, the complications of impacting globally on immune function, as often the case for biologics, remain. For example, the Jakinib XELJANZ (tofacitinib) is licensed for use in rheumatoid arthritis, but comes with an FDA boxed warning for serious infections and malignancies. There is therefore a need for the development of novel, and more specific approaches for immune modulation in the clinic. The most refined form of immunotherapy for autoimmune and allergic diseases, and potentially for transplant rejection, can be provided by only targeting those relatively few lymphocytes that are driving the unwanted immune response. Antigen-based immunotherapy for the induction of immune tolerance therefore remains a holy grail. Here, MacLeod and Current Opinion in Pharmacology 2015, 23:1–3
Anderton consider the progress that has been made in understanding the cellular and molecular basis for antigen-based immunotherapy (predominantly from mouse models) and challenges that remain for the most effective clinical translation. Recent mechanistic studies into antigen-based tolerance point to epigenetic changes in tolerant T cells. One key obstacle, in the clinical scenario, is the need to identify those rare T cells that respond to the antigen, before they can be targeted specifically. This will be important to determine which antigens should be used for therapy, and subsequently whether tolerance has been instilled in those T cells. It might in fact be necessary to monitor the behavior of these T cells over time to identify when tolerance might be waning, which would be a prompt for further therapeutic intervention. Bacher and Scheffold review new flow cytometric technologies that can identify antigen-responsive T cells in peripheral blood to facilitate this important adjunct to immunotherapy. Finally, novel concepts have recently been developed suggesting innovative approaches for the modulation of immunity. There have been many reports of epigenetic changes molding a developing immune response, and that aberrations in these processes might be associated with autoimmune and allergic diseases [7,8]. Whether epigenetic-modifiers, targeting either histone or DNAmodifications can be used therapeutically remains an uncertain, but exciting prospect [9]. A complementary means of controlling cellular function is through microRNA function. Jeker and Marone discuss the prospects and challenges for manipulating microRNA activity therapeutically. Another new line of possibilities has also been recently illuminated with the discovery of new subsets of regulatory cells. Here, Simon Fillatreau discusses the recent area of regulatory function provided by B cells. This is mediated through their expression of the immunosuppressive cytokines IL-10 and IL-35 and the molecular basis for this is considered. Promoting the differentiation of these cells might provide a useful alternative for controlling unwanted immunity. Indeed, whilst the control of pathogenic lymphocytes is an important goal in immune-modulation, increasing evidence suggests that it might be necessary to promote immune suppressive mechanisms to achieve a cure for chronic inflammatory diseases. Enhancing the activity of regulatory lymphocyte populations, including various T cell [10] or B cell populations with regulatory function seems a promising strategy to reach this goal. Together, the areas covered in this issue provide complementary opportunities for designing advanced immunotherapeutics for the future.
References 1.
Bell GM, Reynolds G, Isaacs JD: Biologic therapies in nonrheumatic diseases: lessons for rheumatologists? Nat Rev Rheumatol 2011, 7:507-516. www.sciencedirect.com
Please cite this article in press as: Anderton SM, Fillatreau S: Editorial overview: Immunomodulation: New insights for future treatments, Curr Opin Pharmacol (2015), http://dx.doi.org/10.1016/ j.coph.2015.06.005
COPHAR-1435; NO. OF PAGES 3
Editorial overview Anderton and Fillatreau 3
2.
Eggermont AM, Maio M, Robert C: Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies. Semin Oncol 2015, 42:429-435.
6.
Kontzias A, Kotlyar A, Laurence A, Changelian P, O’Shea JJ: Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 2012, 12:464-470.
3.
Maleki LA, Baradaran B, Majidi J, Mohammadian M, Shahneh FZ: Future prospects of monoclonal antibodies as magic bullets in immunotherapy. Hum Antibodies 2013, 22:9-13.
7.
Gupta B, Hawkins RD: Epigenomics of autoimmune diseases. Immunol Cell Biol 2015, 93:271-276.
8.
4.
Kaiser PD, Maier J, Traenkle B, Emele F, Rothbauer U: Recent progress in generating intracellular functional antibody fragments to target and trace cellular components in living cells. Biochim Biophys Acta 2014, 1844:1933-1942.
Harb H, Renz H: Update on epigenetics in allergic disease. J Allergy Clin Immunol 2015, 135:15-24.
9.
Picascia A, Grimaldi V, Pignalosa O, De Pascale MR, Schiano C, Napoli C: Epigenetic control of autoimmune diseases: from bench to bedside. Clin Immunol 2015, 157:1-15.
5.
Wu X, Shi Y, Ren P, Wang D, Li G: Exploring the relationship between sequences, structures, dynamical behaviors and functions of new type protein drugs: DARPins. Curr Pharm Des 2013, 19:2308-2317.
www.sciencedirect.com
10. Edozie FC, Nova-Lamperti EA, Povoleri GA, Scotta C, John S, Lombardi G, Afzali B: Regulatory T-cell therapy in the induction of transplant tolerance: the issue of subpopulations. Transplantation 2014, 98:370-379.
Current Opinion in Pharmacology 2015, 23:1–3
Please cite this article in press as: Anderton SM, Fillatreau S: Editorial overview: Immunomodulation: New insights for future treatments, Curr Opin Pharmacol (2015), http://dx.doi.org/10.1016/ j.coph.2015.06.005
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Immunomodulation: New insights for future treatments Stephen M Anderton and Simon Fillatreau Current Opinion in Pharmacology 2015, 23:xx–yy
http://dx.doi.org/10.1016/j.coph.2015.06.005 1471-4892/Published by Elsevier Ltd.
Stephen M Anderton
University of Edinburgh, MRC Centre for Inflammation Research, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK e-mail: [email protected] Steve Anderton is Professor of Therapeutic Immunology at the University of Edinburgh. He leads on the theme of ‘‘Immune Modulation and Regulation of Inflammation’’ at the Medical Research Council Centre for Inflammation Research. His main research focus is on the signals that lead to activation or tolerance in T cells that cause autoimmune and allergic disease.
Simon Fillatreau
Deutsches Rheuma-Forschungszentrum, a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany e-mail: [email protected] Simon Fillatreau studied biology at Ecole Normale Superieure de la rue d’Ulm, in Paris, and did his PhD in the laboratory of Prof. David Gray, at the University of Edinburgh, UK. Since 2003, he is group leader at the Deutsches Rheuma-Forschungszentrum, a Leibniz Institute in Berlin, Germany. His group is interested in the processes regulating immune responses to pathogens and self-antigens. www.sciencedirect.com
Chronic inflammatory diseases including autoimmune and allergic disorders cause major disability, and their incidence is dramatically increasing. Current predictions from the World Health Organization estimate that 50% of the world population will be affected by at least one allergic disease by 2050. Whilst we remain without curative treatments for these diseases, recent years have seen a considerable increase in immunotherapeutic options that are available. These include biologics targeting effector molecules or defined sub-populations of immune cells that cause inflammatory pathology, as well as small molecule inhibitors targeting intracellular signaling molecules with key role in these pathologies. In addition, novel approaches based on a better understanding of immune regulation mechanisms are emerging, which might eventually deliver more-specific approaches for treating these chronic inflammatory diseases. This issue aims to provide an overview of these various types of treatments for immune modulation, from those already applied in the clinic, to those that are still in development and may deliver novel forms of immunotherapies in the future. Since TNF-a-blockade provided a proof-of-principle that disrupting a single molecule in a key inflammatory pathway could result in a marked amelioration of chronic inflammatory disease, targeted immunotherapy through use of biologic drugs has evolved into a multi-$billion industry [1]. In cancer, where immunomodulation needs to enhance rather than degrade immunity, the advent of inhibitory checkpoint release using biologic agents also promises to be transformative [2]. Besides the growing number of possible targets for such approaches, technological advances, such as the development of nanobodies, intrabodies and designed ankyrin repeat proteins (DARPins) are providing new ways to use this class of drugs, which promise an even broader application [3–5]. An optimal use of these therapeutic approaches requires that the patients who would benefit from their application can be robustly identified. Whilst this important issue is true for various biologics-disease combinations, it can be exemplified in the use of TNF-a-blockers in Crohn’s disease. Here, Markus Neurath describes how recent advances in clinical molecular imaging can provide a critical stepchange in delivering these blockers in a personalized manner by identifying those patients with the most pronounced TNF-a signature as the most likely to benefit from these treatments. It is likely that similar imaging-based approaches should be applicable to other molecular targets in diseases affecting tissues at body surfaces, including other gastrointestinal disorders as well as inflammatory diseases of the lung and genitourinary tract. Beyond targeting key inflammatory cytokines, biologics are also used to target specific immune cell types. Such approaches can lead to an elimination of most Current Opinion in Pharmacology 2015, 23:1–3
Please cite this article in press as: Anderton SM, Fillatreau S: Editorial overview: Immunomodulation: New insights for future treatments, Curr Opin Pharmacol (2015), http://dx.doi.org/10.1016/ j.coph.2015.06.005
COPHAR-1435; NO. OF PAGES 3
2 Immunomodulation
of the cells within an entire lymphocyte subset, such as B cells after treatment with rituximab. A major drawback of such an approach, as well as of those that block specific homing molecules, is that they lead to a global impairment in immunity, including protective immunity against potentially fatal infectious agents, and they usually only eliminate drivers of the disease without restoring immune-regulatory mechanisms to a sufficient degree to provide a stable restoration of a healthy immune system, therefore requiring prolonged treatment, and consequently persistent immune suppression. In this issue, Lucienne Chatenoud discusses these various strategies, taking into accounts the risk-benefit considerations that are required with the use of biologics, and introduces the possibility of using a distinct class of biologic agents that can achieve a restoration of immune tolerance. Despite the advent of biologics, which revolutionized the treatment of chronic inflammatory disorders, the development of new pharmacological inhibitors remains a highly promising avenue to obtain novel drugs for these diseases. Resorting to small molecule drugs may in fact be a necessary alternative. Together, the increasing prevalence of chronic inflammatory disorders, the fact that currently available drugs must be applied life-long, and the cost of biologics, mean that biologic drugs might ultimately place too great a financial strain on health care providers; a question that is important to bear in mind. More affordable small molecules therefore remain an important alternative, particularly if they can match the efficacy seen with biologics. An added advantage of such an approach might be oral rather than parenteral delivery. Janus kinases (Jaks) are essential signaling intermediates downstream of type I and type II cytokine receptors. The development of a series of Jak inhibitors (Jakinibs) has recently paved the way to the application of kinase inhibitors in immunomodulation of autoimmune disease [6]. Another family of kinases, the PI3 kinases, plays major roles in immune cell functions and Klaus Okkenhaug et al. discuss the prospects of targeting these therapeutically. Despite the advantages that might come from the use of small molecule modulation of immune cell signaling pathways, the complications of impacting globally on immune function, as often the case for biologics, remain. For example, the Jakinib XELJANZ (tofacitinib) is licensed for use in rheumatoid arthritis, but comes with an FDA boxed warning for serious infections and malignancies. There is therefore a need for the development of novel, and more specific approaches for immune modulation in the clinic. The most refined form of immunotherapy for autoimmune and allergic diseases, and potentially for transplant rejection, can be provided by only targeting those relatively few lymphocytes that are driving the unwanted immune response. Antigen-based immunotherapy for the induction of immune tolerance therefore remains a holy grail. Here, MacLeod and Current Opinion in Pharmacology 2015, 23:1–3
Anderton consider the progress that has been made in understanding the cellular and molecular basis for antigen-based immunotherapy (predominantly from mouse models) and challenges that remain for the most effective clinical translation. Recent mechanistic studies into antigen-based tolerance point to epigenetic changes in tolerant T cells. One key obstacle, in the clinical scenario, is the need to identify those rare T cells that respond to the antigen, before they can be targeted specifically. This will be important to determine which antigens should be used for therapy, and subsequently whether tolerance has been instilled in those T cells. It might in fact be necessary to monitor the behavior of these T cells over time to identify when tolerance might be waning, which would be a prompt for further therapeutic intervention. Bacher and Scheffold review new flow cytometric technologies that can identify antigen-responsive T cells in peripheral blood to facilitate this important adjunct to immunotherapy. Finally, novel concepts have recently been developed suggesting innovative approaches for the modulation of immunity. There have been many reports of epigenetic changes molding a developing immune response, and that aberrations in these processes might be associated with autoimmune and allergic diseases [7,8]. Whether epigenetic-modifiers, targeting either histone or DNAmodifications can be used therapeutically remains an uncertain, but exciting prospect [9]. A complementary means of controlling cellular function is through microRNA function. Jeker and Marone discuss the prospects and challenges for manipulating microRNA activity therapeutically. Another new line of possibilities has also been recently illuminated with the discovery of new subsets of regulatory cells. Here, Simon Fillatreau discusses the recent area of regulatory function provided by B cells. This is mediated through their expression of the immunosuppressive cytokines IL-10 and IL-35 and the molecular basis for this is considered. Promoting the differentiation of these cells might provide a useful alternative for controlling unwanted immunity. Indeed, whilst the control of pathogenic lymphocytes is an important goal in immune-modulation, increasing evidence suggests that it might be necessary to promote immune suppressive mechanisms to achieve a cure for chronic inflammatory diseases. Enhancing the activity of regulatory lymphocyte populations, including various T cell [10] or B cell populations with regulatory function seems a promising strategy to reach this goal. Together, the areas covered in this issue provide complementary opportunities for designing advanced immunotherapeutics for the future.
References 1.
Bell GM, Reynolds G, Isaacs JD: Biologic therapies in nonrheumatic diseases: lessons for rheumatologists? Nat Rev Rheumatol 2011, 7:507-516. www.sciencedirect.com
Please cite this article in press as: Anderton SM, Fillatreau S: Editorial overview: Immunomodulation: New insights for future treatments, Curr Opin Pharmacol (2015), http://dx.doi.org/10.1016/ j.coph.2015.06.005
COPHAR-1435; NO. OF PAGES 3
Editorial overview Anderton and Fillatreau 3
2.
Eggermont AM, Maio M, Robert C: Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies. Semin Oncol 2015, 42:429-435.
6.
Kontzias A, Kotlyar A, Laurence A, Changelian P, O’Shea JJ: Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol 2012, 12:464-470.
3.
Maleki LA, Baradaran B, Majidi J, Mohammadian M, Shahneh FZ: Future prospects of monoclonal antibodies as magic bullets in immunotherapy. Hum Antibodies 2013, 22:9-13.
7.
Gupta B, Hawkins RD: Epigenomics of autoimmune diseases. Immunol Cell Biol 2015, 93:271-276.
8.
4.
Kaiser PD, Maier J, Traenkle B, Emele F, Rothbauer U: Recent progress in generating intracellular functional antibody fragments to target and trace cellular components in living cells. Biochim Biophys Acta 2014, 1844:1933-1942.
Harb H, Renz H: Update on epigenetics in allergic disease. J Allergy Clin Immunol 2015, 135:15-24.
9.
Picascia A, Grimaldi V, Pignalosa O, De Pascale MR, Schiano C, Napoli C: Epigenetic control of autoimmune diseases: from bench to bedside. Clin Immunol 2015, 157:1-15.
5.
Wu X, Shi Y, Ren P, Wang D, Li G: Exploring the relationship between sequences, structures, dynamical behaviors and functions of new type protein drugs: DARPins. Curr Pharm Des 2013, 19:2308-2317.
www.sciencedirect.com
10. Edozie FC, Nova-Lamperti EA, Povoleri GA, Scotta C, John S, Lombardi G, Afzali B: Regulatory T-cell therapy in the induction of transplant tolerance: the issue of subpopulations. Transplantation 2014, 98:370-379.
Current Opinion in Pharmacology 2015, 23:1–3
Please cite this article in press as: Anderton SM, Fillatreau S: Editorial overview: Immunomodulation: New insights for future treatments, Curr Opin Pharmacol (2015), http://dx.doi.org/10.1016/ j.coph.2015.06.005
