U.S. Food and Drug Administration and the New York Academy of Sciences
Cytokine Therapies: Novel Approaches for Clinical Indications
Posted July 02, 2009
Cytokine therapies have tremendous potential for treating a variety of diseases. These intercellular messengers are involved in activating numerous processes in the body in virtually all cell types, but they are perhaps best known for their role in recruiting and activating immune cells in response to injury and infection.
The therapeutic potential of cytokines was recognized decades ago, but attempts to use cytokines as pharmaceutical agents have been mixed. Scientists have come to realize that they need a better understanding of cytokine biology and must develop targeted delivery methods to improve treatment efficacy. In addition, cooperation between regulatory agencies, pharmaceutical companies, doctors and basic researchers is critical to driving the field forward.
Researchers from academia and industry came together with FDA scientists and regulators at the New York Academy of Sciences on March 26–27, 2009 to discuss these issues and their latest research.
Use the tabs above to find a meeting report and multimedia from this event.
- 00:011. Introduction
- 03:242. Activation vs. homeostatic cytokines; Lymphoid microenvironment; IL-7 response to T cell depletion
- 09:123. Phase I study of rhIL7
- 13:304. IL-2 vs. IL-7; Cell expansion; TREC increases
- 20:335. Preclinical and clinical data thus far; Further development
- 25:526. Potential therapeutic applications
- 28:317. Conclusion and acknowledgement
- 00:011. Introduction
- 03:452. IFN-lambda1 receptor distribution; Cell specificity
- 05:203. Regulation of HepG2 gene; Inducement by IFN-lambda1
- 06:464. ISG induction; PEG-IFN-lambda1; Safety and efficacy
- 11:065. In vivo preclinical background; Preclinical toxicology overview
- 14:376. Clinical trials
- 20:027. Adverse events; Summary of Phase 1 data
- 21:288. Overall summary and concluding remark
- 00:011. Introduction
- 03:582. Exposure of monocytes to SLE serum
- 07:443. Disease stages
- 14:024. Relevance of Type-I IFN pathway to "drug-induced" lupus; The IFN signature as biomarker
- 20:525. Monitoring disease progression; Nanostring assay
- 23:176. Juvenile Idiopathic Arthritis (JIA)
- 27:437. ANAJIS study design; Heterogeneous course
- 31:458. Conclusion and acknowledgement
- 00:011. Introduction
- 01:052. Rate of glycolysis in a liver tumor exceeds that in the brain
- 02:413. Model of tumor progression
- 06:444. IL-2 background and as cancer therapy
- 12:075. The case for high-dose IL-2 therapy
- 15:516. IL-2 mechanism
- 16:347. Safety of high-dose IL-2
- 18:088. HMGB1 release
- 20:549. New findings in IL-2 therapy
- 23:4310. Metabolism and autophagy
- 29:0511. Conclusion and acknowledgement
- 00:011. Introduction; Pathophysiology of rheumatoid arthritis
- 06:202. Therapeutic advances; Model for synovitis
- 08:433. Anti-TNF therapies; Studies
- 14:594. Remission induction as a goal; The BeSt study
- 21:205. Cytokine profiling; Differences between therapies
- 24:486. Immunogenicity of biological therapies; Safety
- 30:217. Other approved biologics
- 32:358. Emerging therapies; Signal transduction inhibitors
- 35:589. Summary; Opportunities and challenge
- 00:011. Introduction; History of IL-1Ra
- 04:402. Familial Cold Autoinflammatory Syndrome and Muckle Wells Syndrome
- 07:213. Inflammasome; Blocking IL-1 in NOMID; High-resoluion imaging
- 12:164. Hearing data; Vision data; Bony lesions
- 16:395. Rilonacept; IL-1 trials
- 19:446. A patient referral...; Anakinra
- 26:107. Comparison NOMID-DIRA; Diseases with IL-1 features
- 27:518. Summary and acknowledgement
The International Society for Interferon and Cytokine Research
A research society dedicated to cytokine research.
The Society for Leukocyte Biology
A research society devoted to the study of the cellular biology of leukocytes and cytokines.
FDA's Critical Path Initiative
An effort to facilitate the modernization of the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery into a therapeutic product.
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Ahmad A. Tarhini
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M. Virginia Pascual
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Raymond P. Donnelly, PhD
Raymond Donnelly is a senior investigator in the Division of Therapeutic Proteins at the FDA Center for Drug Evaluation & Research (CDER) in Bethesda, MD. After completing postdoctoral training in immunology at the Boston University School of Medicine, he joined the FDA Division of Cytokine Biology in 1989. Donnelly serves as an expert on product manufacturing issues pertaining to a variety of therapeutic proteins, including many cytokines and cytokine antagonists. He also manages a laboratory research program that is focused on defining the receptors for and biological activities of novel cytokines. Donnelly is a current or former member of several editorial boards, including the Journal of Immunology, Journal of Interferon & Cytokine Research, and Genes & Immunity. He was the 2005 recipient of the FDA Scientific Achievement Award for Excellence in Laboratory Science.
Amy Rosenberg, MD
Amy Rosenberg has worked at the FDA for twenty years, in cellular therapies and therapeutic vaccines, as well as protein therapeutics. She became Director of the Division of Therapeutic Proteins in CDER's Office of Biotechnology Products (OBP) in1999. Her major interests are in immune tolerance induction in the setting of transplantation and neutralizing antibody responses to protein therapeutics, as well as in novel vaccine platforms.
Howard A. Young, PhD
Howard Young, a principal investigator in the Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick studies the control of gene expression during the development and maturation of the cellular immune system with a special emphasis on Interferon-gamma expression by NK cells. Author/co-author of over 270 papers, Young was president, International Society for Interferon and Cytokine Research (2004–2005) and served as chair of the Immunology Division of the American Society for Microbiolgy. He has twice served as chair of the NIH Cytokine Interest Group and co-chair of the NIH Immunology Interest Group. Young is a two-time recipient of the NIH Director's Award for Mentoring (2000, 2006) and in 2006 received the National Public Service Award. In 2007 he was named deputy chief, Laboratory of Experimental Immunology, Cancer and Inflammation Program, NCI-Frederick, Frederick, MD.
Kathy Granger, PhD
Kathy Granger manages the Life Science conferences at The New York Academy of Sciences. Granger received her PhD from the Department of Medicine, Monash University, Australia. She worked as a postdoctoral associate at Weill Cornell Medical College in New York City before joining the New York Academy of Sciences as program manager for Life Sciences.
Abraham Abuchowski, PhD
Abraham Abuchowski, is founder and CEO of Prolong Pharmaceuticals. Abuchowski was the founder and past chairman and CEO of Enzon, Inc., biopharmaceutical company that specializes in PEGylation technology. During his 13 years at Enzon (1983–1996), Abuchowski successfully commercialized PEGylation by gaining FDA approval for three protein-based biopharmaceuticals. Abuchowski was instrumental in helping Enzon mature from a developmental stage company to a fully integrated publicly traded biopharmaceutical company.
Abuchowski holds a PhD in biochemistry from Rutgers University. He is an internationally recognized authority on biopharmaceutical delivery and has published more than 100 scientific papers and several book chapters on therapeutic products.
Ernest C. Borden, MD
Ernest Borden's laboratory studies melanoma, sarcomas, and new cancer therapies such as interferons, vaccines, and antibodies. In addition to developing improved approaches to clinically assess interferons and their inducers, he focuses on the function and action of genes that are stimulated by interferons and on the anti-tumor effects of other protein therapeutics. He has published over 200 articles and book chapters on interferons. Borden has an international reputation for research and treatment of melanomas and sarcomas. He received the Milstein Award from the International Society of Interferon and Cytokine Research (ISICR) in 2004, and an American Cancer Society Distinguished Service Award in 1984.
ShaAvhree Buckman, MD, PHD
ShaAvhree Buckman is the director of the Center for Drug Evaluation and Research at the Food and Drug Administration.
William E. Carson, III, MD
William Carson is a professor of surgery and associate director for clinical research at Ohio State University in Columbus. His research addresses the mechanism of action of cytokine therapy in the setting of malignancy. His lab addresses three major projects that began as basic in vitro observations and are now translated into the clinical setting: 1) the use of cytokines to enhance the actions of interferon-alpha (IFN-alpha), 2) the use of cytokines to enhance the actions of anti-tumor monoclonal antibodies, and 3) the effects of stress on the immune system of patients diagnosed with cancer.
Ken Chang, PhD
Kathleen Clouse, PhD
Kenneth A. Dawson, PhD
Kenneth Dawson is chair of physical chemistry within the UCD School of Chemistry and Chemical Biology. An experienced and multi-award-winning researcher, his focus in on groundbreaking projects that are exploring the nature of the interaction between nanoscale structures and living matter, such as cells and tissue. Dawson also has a significant involvement in policy making. He represents Ireland on the PESC (Physical & Engineering Sciences Committee) of the European Science Foundation; is a European board member of the International Council of Nanotechnology (ICON); an external board member of the Complexity Centre at Rome University (La Sapienza); and is also an advisor to a number of governments and agencies in EU and the U.S. on the health-related issues of nanoscience, and nanomedicine.
Michael J. Elliott, PhD
Raphaela Goldbach-Mansky, MD
Raphaela Goldbach-Mansky is acting chief of the Translational Autoinflammatory Disease Section at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. Goldbach-Mansky received her medical degree from the University Witten-Herdecke, Germany, in 1990 and completed a combined residency in Internal Medicine and Pediatrics at Case Western University, Metro Health Medical Center. She completed her rheumatology fellowship training at NIAMS in 1999.
Goldbach-Mansky is currently a tenure track investigator at NIAMS. Her research studies the effect of targeted immune-modulatory agents in adult and pediatric patients with autoinflammatory diseases with particular emphasis in understanding the disease pathogenesis. In a number of natural history and interventional studies she tries to learn about the extent of the inflammatory disease manifestations and long term disease outcome.
Steven M. Holland, MD
Steven Holland is chief of the Laboratory of Clinical Infectious Diseases at the Nation Institute of Allergy and Infectious Diseases, NIH. His team conducts clinical and basic studies of important human recurrent or chronic infectious and immunologic diseases with a goal of developing a comprehensive understanding of disease history, pathogenesis, pathophysiology, and management. The laboratory focus on mycobacterial, bacterial, viral, and fungal infections, as well as the acquired and congenital immune disorders associated with infection susceptibility and resistance. His program integrates clinical, cellular, and molecular investigation, including animal models and human natural history and therapeutic trials.
Steven Kozlowski, MD
Steven Kozlowski is the director of the Office of Biotechnology Products in the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD.
Michael T. Lotze, MD
Michael Lotze is professor of surgery and bioengineering and vice chair of research of the Department of Surgery at the University of Pittsburgh Schools of the Health Sciences. He has 35 years experience in the field of Immunology and clinical medicine and has a fundamental understanding of both cancer biology and immunology. Dr. Lotze's laboratory focuses on the role of necrotic cell death and how it modifies immunity and the biology of inflammation and cancer as well as cellular immunotherapy using cytokines, natural killer cells, and dendritic cells. He is the co-inventor on 10 patents in dendritic cell vaccines and antigen discovery and has over 500 publications which include peer reviewed journals and book chapters.
Dennis M. Miller, PhD
Dennis Miller is vice president of preclinical development at ZymoGenetics. He has worked in the pharmaceutical and biotechnology industries since 1992. Miller has participated in the research and development of numerous therapeutic drug candidates by characterizing the pharmacologic and toxicologic properties of these experimental medicines in both the preclinical and clinical settings. For the past several years, he has lead efforts to explore the therapeutic utility of two cytokines discovered at ZymoGenetics, namely interleukin 21 and interferon lambda (interleukin 29).
Larry W. Moreland, MD
Larry Moreland is a professor of medicine with the Division of Clinical Immunology and Rheumatology and director of the Arthritis Clinical Intervention Program at the University of Pittsburgh Medical Center. Moreland's areas of specialty include scleroderma, rheumatoid arthritis, osteoarthritis and other connective tissue diseases. He is board certified in clinical immunology and rheumatology and internal medicine. Moreland received his medical degree from West Virginia University School of Medicine before completing his internship and residency with West Virginia University Hospital.
Ushma Savla Neill, PhD
Ushma Neill is executive editor of the Journal of Clinical Investigation. Neill obtained her PhD in biomedical engineering from Northwestern University with Christopher M. Waters, studying airway physiology and mathematical models of wound healing. After a brief postdoc with Peter H. S. Sporn studying pulmonary eosinophilia, Neill won the Marshall Sherfield Postdoctoral Fellowship. As a Sherfield Fellow, she studied the mechanics of vascular permeability with C. Charles Michel at Imperial College, London. Neill returned to the U.S. in 2001, and after 2 years as an editor at Nature Medicine, she joined the Journal of Clinical Investigation in March, 2003.
Virginia Pascual, MD
Virginia Pascual is an investigator at Baylor's Institute for Immunology and Research and adjunct associate professor of biomedical studies at Baylor University. She studies breakdowns of the immune system leading to autoimmune conditions, such as lupus, rheumatoid arthritis and systemic onset juvenile idiopathic arthritis. In her clinical practice, she specializes in Pediatric Rheumatology and is concerned with autoimmune diseases in children. In 1995, Pascual was awarded the Senior Rheumatology Scholar Award from the American College of Rheumatology.
Allen Radin, MD
Richard M. Ransohoff, MD
Richard Ransohoff is director of the Neuroinflammation Research Center in the Department of Neurosciences of Lerner Research Institute, professor of molecular medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University; and staff neurologist in the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio.
For the past decade, Ransohoff's research has focused on the functions of chemokines and chemokine receptors in development and pathology of the nervous system. He also has a longstanding and continuing interest in the mechanisms of action of interferon-beta. Ransohoff has published more than 150 scientific reports, more than 50 reviews and book chapters, and edited three books. Among multiple honors and awards, Ransohoff was elected to the American Association of Physicians in 2006, he received the Cleveland Clinic Lerner Research Institute's Award for Excellence in Science in 2006, and was elected a fellow of the American Association for the Advancement of Science in 2007.
Kendall A. Smith, MD
Kendall Smith is the Rochelle Belfer Professor of Medicine and Immunology at Cornell University's Weill Medical College and Graduate School of Biomedical Sciences and senior attending physician and chief of the Division of Immunology at the New York Presbyterian Medical Center. Smith's research team created the first monoclonal T cells, which enabled them to discover the interleukin 2 (IL-2) molecule, and the interleukin 2 receptor (IL-2R). These advances led them to develop IL-2 as an immunotherapy, and as a potential adjuvant for vaccines, to boost T cell immune responses. Smith has recently introduced a new theory of how the immune system functions, "The Quantal Theory of Immunity" that is based on the understanding of the IL-2/IL-2R system.
Neil Stahl, PhD
Neil Stahl has been senior vice president of Research and Development Sciences since January 2007. Prior to that date, he served as senior vice president of Preclinical Development and Biomolecular Sciences, a position he held since December 2000. Prior to that date, he was vice president, Preclinical Development and Biomolecular Sciences, a position he held since January 2000. He joined the Company in 1991. Before becoming vice president of Biomolecular Sciences in July 1997, Stahl was director of Cytokines and Signal Transduction. Stahl received his PhD in Biochemistry from Brandeis University.
Lothar Steidler, PhD
Lothar Steidler is senior director of technology development and member of the senior management of ActoGeniX NV in Zwijnaarde, Belgium and guest professor at Ghent University. Steidler's department engineers novel recombinant Lactococcus lactis, designed for in vivo production of therapeutic proteins (cytokines, peptides, allergens, ect.). Steidler has invented and pioneered "TopAct" technology: the use of recombinant microflora for topical and active delivery of proteins. The development of a robust environmental containment system enabled his team to advance their lead product into the first clinical studies ever, using genetically modified microorganisms as therapeutics. Steidler has published 35 papers and is the main inventor on 9 patent families that cover TopAct technology. Steidler has received the Biogent-Plant Genetic Systems Award (Belgium, 1987), the BBSRC Underwood Award (U.K., 1995) and the William Grant & Sons Young European prize for Invention and Discovery (U.K., 2001).
Julian A. Symons, DPhil
Julian Symons is associate director at Roche Palo Alto. Symons obtained his DPhil from the University of York, UK, in 1986. Following this he undertook 13 years of academic research within the Departments of Medicine at the University of Edinburgh, University of Sheffield, and the Sir William Dunn School of Pathology, University of Oxford. In 1999 he joined the Pharmaceutical Division of Hoffmann La Roche in the UK to work on interferon and hepatitis C virus. Symons is presently the head of Hepatitis C Virus Biology at the Hoffmann La Roche Palo Alto research site in California, USA. Symons has published more than 120 full papers, review articles, and abstracts in the areas of cytokine/interferon research, autoimmune disease, viral immune evasion, and antiviral drug discovery.
Ahmad A. Tarhini, MD
University of Pittsburgh Cancer Institute
Ahmad Tarhini is a senior hematology/oncology fellow at the University of Pittsburgh Cancer Institute.
Daniela Verthelyi, MD, PhD
Daniela Verthelyi received her MD from the University of Buenos Aires and a PhD from the Virginia Tech. She then completed a fellowship training in Immunology at the Section in Viral Immunology at the Center for Biologics Evaluation and Research of the FDA before joining the Division of Therapeutic Proteins and eventually becoming the chief of the Laboratory of Immunology in the same group. She has authored over 50 peer reviewed articles, chaired the NIH/FDA Cytokine interest Group, and received of the FDA's ‘Excellence in Laboratory Sciences" award, among other honors.
Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.
This activity is supported by an educational donation provided by:
This conference has been made possible through the generous support of the following organizations:
Can better animal models be developed to study the action of cytokines?
What can be learned from "human translational data" that comes from studying populations that have inborn cytokine defects?
How can the scientist-clinician collaboration be improved so that information flows more freely from bedside to bench in addition to the reverse direction?
What is the role of the microbiome in modulating the immune system?
How can cytokine formulations be improved so that a one-size-fits-all approach doesn't have to be used?
How can cytokines or cytokine antagonists be delivered more directly to the tissues or organs where they would be most effective?
Can gene therapy be used for site-specific delivery?
How can researchers enhance the half-life of cytokines without increasing the risk of adverse effects?
Is development of antibodies to a cytokine always a bad thing? How can the immunogenicity of cytokines be minimized?
How can sample collection and cytokine measurements be better standardized so that researchers can compare results from clinical studies conducted at different sites?
- Adding polyethylene glycol to molecules can greatly improve their half-life in the body and enhance other pharmacologically important properties such as solubility.
- Nanoparticles might facilitate targeted delivery of cytokines.
- Cytokines can be delivered to the gut using genetically engineered bacteria, providing a viable delivery mechanism for the treatment of inflammatory bowel disease.
- Targeted delivery can be enhanced when cytokines are attached to PEG and targeting antibodies via a "dock-and-lock" system.
Introduction to delivery and pharmacokinetic problems
Though cytokine therapeutics have defined biological activities that could contribute to disease amelioration or cure, they pose two major challenges: first, they have very rapid in vivo kinetics, and second, they can induce a multitude of effects, given the broad expression of cytokine receptors on many different cells in the body. Cytokines are rapidly eliminated, both by receptor-mediated uptake as well as by enzymatic inactivation. The very short half-lives of these agents significantly reduces their efficacy. Increasingly the stability of these biological agents would allow these cytokine drugs to be given less frequently and at lower doses.
Because these therapies are identical to naturally occurring cytokines, they have multiple effects on cells of the immune system, as well as non-immune system cells, leading to unwanted toxicities. A more selective means of drug delivery might help reduce many of the toxic and undesirable side effects of these agents.
Researchers have developed several mechanisms for extending the half-life of cytokines and targeting them to specific organs or regions in the body.
Polyethylene glycol (PEG) extends the half-life of cytokines
The addition of polyethylene glycol (PEG) to proteins can greatly improve their half-life in the body and enhance other pharmacologically important properties such as their solubility. Pegylation, as it is now called, was pioneered by Abraham Abuchowski of Prolong Pharmaceuticals, while a PhD student at Rutgers University. It is now a standard approach to prolonging in vivo activity of biological therapeutics in the pharmaceutical industry.
Pegylation has a number of benefits. It is non-toxic and enhances the circulating life of drugs thereby reducing the number of doses and the frequency of dosing. Adding PEG causes molecules to become more water-soluble because PEG binds water readily, creating a hydrodynamic shell that doesn't seem to interfere with binding to receptors.
Numerous methods have been developed to attach PEG to protein and non-protein molecules. However, Abuchowski noted that PEG must be added in a way as to preserve the biological activity of the protein drug, making the addition of PEG to a protein as much an art as a science.
Nanoparticles for targeted delivery of cytokines
Nanoparticles are another promising innovation that may help improve the bioactivity of cytokines, said Anna Salvati of the Centre for BioNano Interactions School of Chemistry and Chemical Biology, University College Dublin. These synthetic spheres are just tens of nanometers in diameter.
Nanoparticles represent a novel way to introduce bioactive proteins into compartments in the body that are difficult to reach. Due to their small size, they can diffuse through the blood brain barrier, enter cells, and even enter the nuclei of cells. Placing drugs into nanoparticles protects them from degradation, thereby increasing the half-life, permitting lower doses, and decreases potential toxicity.
The challenge is to create particles that can transport drugs to targets where they will release their contents. These researchers created nanosized beads and coated them with proteins that can selectively target and bind to cell-surface proteins or be taken up by cells where they interact with intracellular proteins and deliver their cargo.
Cytokine delivery via food-grade bacteria
One novel delivery system enables oral delivery of therapeutic peptides and proteins via genetically engineered bacteria. Pioneered by Lothar Steidler and his team at ActoGeniX NV in Belgium, these noninvasive, noncolonizing food-grade bacteria secrete bioactive proteins and peptides into the gastrointestinal tract. These ActoBiotics are a type of bacteria called Lactococcus lactis that are engineered in such a way as to prevent survival outside of the body.
The company has used this novel delivery method to deliver recombinant human IL-10 to the gut for the successful treatment of inflammatory bowel disease (IBD). This cytokine was tested in the past for treatment of IBD, but it was given intravenously, and with its short half life, probably did not reach the critical target area, the mucosal lining of the gut. In the initial studies performed in the mid-1990s, parenteral administration of IL-10 at high concentrations proved to be toxic but the use of Lactococcus to deliver IL-10 orally now provides an improved method to deliver this cytokine to the gut, where it suppresses inflammation.
Improved targeting and bioavailability using the dock-and-lock (DNL) method
Ken Chang of Immunomedics described a method that can be adapted to deliver cytokines via site-specific conjugation of molecules using naturally occurring protein-protein interactions. The "dock-and-lock" method allows researchers to design and construct novel compounds that are multispecific, multifunctional, and multivalent. It can be used to attach polyethylene glycol (PEG) molecules to cytokines or attach cytokines to antibodies for targeted delivery to specific tissues in the body.
- IL-2 induces complete remission in 8% to 10% of renal cell carcinoma cancer patients.
- Cytokines activate several pathways that help the body destroy tumor cells through apoptosis and inhibit formation of new blood vessels around the tumor.
- Researchers are gaining a better understanding of how cytokines activate downstream genes that in turn kill tumor cells.
A fresh look at IL-2
The antiproliferative properties of cytokines are mediated via a number of mechanisms. They can be anti-angiogenic, activate immune system cells, and induce expression of genes that are antiproliferative through mechanisms not yet fully understood. Cytokines can also induce apoptosis, a type of programmed cell death. IL-2, for example, can activate cytotoxic T-lymphocytes (CTLs) that secrete a protein called perforin. Perforin pokes holes in the cell membrane and allows preformed proteins called granzymes to enter and induce apoptosis.
IL-2 raised great hopes in the 1990s of providing a treatment or perhaps even a cure for cancer, said Michael T. Lotze of the University of Pittsburgh Cancer Institute. The cytokine causes a durable 8% to 10% remission rate in patients with melanoma and renal cell carcinoma.
In many ways IL-2 is a success story. However, the small percentage of patients in which it demonstrates success is not sufficiently robust. It is thus important to discover the mechanism by which this therapy works in the small subset of responders. A recent study by Howard Kaufman's lab looked at responsiveness and non-responsiveness to IL-2 therapy and found that individuals with high levels of the growth factor VEGF prior to therapy were less likely to respond compared to patients with low concentrations of VEGF in their bloodstream. Similarly fibronectin was high in non-responders but low in responders. These levels could perhaps be used to prospectively identify patients who will respond to IL-2.
Digesting the situation
Another way to understand the low rate of success with IL-2 therapy is to examine it in the context of the cell's response to growth factors and stress. Cancer is essentially a metabolic disorder because the body's metabolism supports tumor formation, said Lotze. The immune system is complicit because it tolerates formation of the tumor and surrounding new blood vessels. Researchers have known for some time that apoptosis is disabled during tumor formation. Lotze believes that a competing cell death process called autophagy occurs when cells are under survival stress. He further noted that VEGF and HMGB1 are important switches, modulating apoptosis and autophagy.
To improve the remission rate of IL-2, a better understanding of how IL-2 works is essential. In addition to induction of apoptosis, IL-2 activates NK cells and macrophages, promotes Th1 cell activity, and induces proliferation of B cells. IL-2 therapy for cancer is also associated with induction of autoimmunity, which, in the setting of IFN-α treatment appears correlated with clinical benefit. "The failure or success of our cytokines is tied closely to our understanding of the science," said Lotze.
Finding the mechanism of cytokine action
Ahmad Tarhini of the University of Pittsburgh Cancer Institute described the clinical and immunological basis of IFN-α therapy in melanoma patients. Melanoma is a highly curable cancer if diagnosed and treated in the early stages of development, but is usually fatal if allowed to metastasize. Some spontaneous regressions occur, suggesting that the innate immune system can fight the disease, perhaps through the involvement of T cells, macrophages and NK cells. The presence of T-cell infiltrates is a positive prognostic marker and the presence of T-cell infiltrates within regional nodal metastasis predict benefit from IFN-α2 therapy.
Tarhini and his colleagues are attempting to discover biomarkers that indicate who will respond effectively to IFN-α treatment. The researchers found that patients with high pretreatment levels of certain pro-inflammatory cytokines (IL-1-α, β; MIP-1-α, β; IL-6; TNF-α) were more likely to have relapse-free survival. Survival after IFN-α treatment was greater in patients who developed autoimmunity (often seen as vitiligo or autoimmune thyroiditis in melanoma patients).
Ernest Borden of the Cleveland Clinic underscored the need to understand the mechanisms that occur downstream of interferon binding to its cell surface receptor. One common downstream signaling pathway is JAK/STAT1 phosphorylation. A drug called stibogluconate (SSG), a small molecular weight molecule, can enhance JAK/STAT1 phosphorylation and increase the activity of therapeutic cytokines such as IFN-α. In combination with IFN-α2, stibogluconate is now being studied in a phase 1 trial in melanoma patients.
Borden indicated that to implement the therapeutic potential of interferons, we must gain a better understanding of the regulation and function of the more than 300 genes induced by this cytokine. Some of these genes are pro-apoptotic, such as TRAIL and XAF1 whereas genes such as G1P3 (ISG 6-16) can silence apoptosis. Many other IFN-inducible genes are immune-modulating or anti-angiogenic.
Understanding the function of interferon-stimulated genes (ISGs) can help researchers define and overcome resistance mechanisms and drug-related toxicities, and lead to improved ways to enhance anti-tumor activity through modification of signaling. "One needs to be open," said Borden, "to new ideas as to how to utilize cytokines as to their ultimate impact."
IL-21 in addition to monoclonal antibodies for the treatment of cancer
A relative newcomer in the cytokine field, IL-21, is also being tested as a cancer therapy agent. This cytokine is secreted by activated CD4+ T cells and Natural Killer (NK) cells. It helps regulate immunoglobulin production and isotype switching by B cells, and has activating effects on macrophages.
IL-21 has demonstrated anticancer properties in mouse studies as well as in early phase clinical trials and has structural homology to other cytokines including IL-2, said William E. Carson III of Ohio State University. In mice, the cytokine mediates anti-tumor effects in models of melanoma, renal cell carcinoma, colon adenocarcinoma, breast cancer, and other tumors. The anti-tumor effects appear to be mediated by NK cells and CD8+ T cells.
Researchers tested IL-21 in combination with trastuzumab (Herceptin, Genentech), a monoclonal antibody that inhibits the growth of Her2/Neu positive tumors and mediates antibody-dependent cellular cytotoxicity (ADCC). They found that IL-21 enhances NK cell-mediated ADCC and cytokine production in conjunction with treatment with monoclonal antibodies rituximab (Rituxan, Genentech) and trastuzumab. "Cytokines can be an extra kick to monoclonal antibody therapy," said Carson.
Since the clinical trials of the 1990s, numerous technological advances have occurred that could revive the potential of these cytokine therapies as viable drug candidates. These include advances in drug delivery platforms and ways to prolong the in vivo half-life of the therapeutic proteins. Biomarkers could now be used to prospectively identify patients who are more likely to respond to therapy. The analytical tools that exist today, including microarray technology for genes and proteins, could help identify better biomarkers of cytokine-mediated pharmacodynamic activities.
Basic investigations into cytokine biology will also improve the therapeutic potential of these proteins. Normally cytokines interact with receptors to initiate downstream signaling cascades that turn on or off key genes that mediate biological activities. Researchers are studying how to determine what genes or groups of genes mediate the effects of cytokines.
Some cytokines that failed clinical trials in the 1990s might be worth reexamining. A promising but all but abandoned cytokine is IL-12. This cytokine was explored for treatment of some infectious diseases and cancer but was found to be highly toxic and largely ineffective as a mono-therapeutic agent in several clinical trials. However, IL-12 might be more effective as an anti-cancer agent if administered at lower, less toxic concentrations together with other anti-cancer drugs or cytokines.
- Endogenous cytokines are involved in inflammation and mediate the immune responses characteristic of autoimmune diseases.
- Monoclonal antibodies that block the activity of cytokines, either by blocking cytokine receptors or neutralizing cytokines' activity, hold great promise for the treatment of autoimmune diseases such as lupus, inflammatory bowel disease, and psoriasis.
- The study of rare autoimmune and inflammatory disorders could provide researchers with knowledge of how cytokines participate in a variety of immune-mediated diseases.
- Gene expression profiling could help researchers understand how cytokines play a role in depressing or exacerbating the inflammation associated with certain autoimmune disorders.
- New methods for targeting and delivering cytokine therapeutics have the potential to improve therapeutic utility and reduce toxicity.
TNF-α inhibitors and rheumatoid arthritis
Cytokines act as messengers to activate or suppress the immune system, so they represent promising therapeutic agents for many diseases that involve the immune system. These diseases include inflammatory diseases characterized by an overproduction of inflammatory cytokines such as IFN-γ or TNF-α, and autoimmune diseases, which are characterized by hyper-immune system responses directed against the body's own proteins or cells.
The treatment of many immune-related disorders has been improved greatly by the discovery of cytokine inhibitors. These include cytokine receptor constructs that can bind to specific cytokines and monoclonal antibodies that target specific cytokines.
Rheumatoid arthritis is a classic example of an inflammatory disease where cytokines play a prominent role. In the joint, when arthritic antigens are present they cause the activation of T cells that in turn produce cytokines such as TNF-α, IL-1, IL-6, IFN-γ, and others. These cytokines in turn mediate the activation of tissue-destroying metalloproteinases, activation of vascular adhesion molecules that recruit lymphocytes, macrophages, and other immune system cells to the joints. A consequence of these events is the activation of B cells which produce auto-antibodies. If unchecked, these processes can lead to progressive joint destruction.
For many patients, rheumatoid arthritis affects systems other than the joints. Patients can suffer from cardiovascular disease, chronic pulmonary obstructive disease (COPD), blood disorders, neurological symptoms, pulmonary effects, and ocular problems.
Larry Moreland at the University of Pittsburgh reviewed ways to target TNF-α, a cytokine involved in rheumatoid arthritis (RA). TNF-α inhibitors have been shown to decrease symptoms, slow disease progression, and improve quality of life in many RA patients.
Five biological agents that inhibit TNF-α are currently approved for use in the USA. Three are monoclonal antibodies (mAbs) against TNF-α and two are receptor constructs that act by binding TNF-α and facilitating its clearance from the body.
TNF-α appears to play a central role in disease activity in roughly three-quarters of all RA patients. It may be that the remaining 25% of patients develop neutralizing antibodies to anti-TNF-α agents after being treated with one or more of these anti-TNF agents for some period of time. Comparative studies to accurately quantify the incidence of anti-TNF antibodies in RA patients treated with different anti-TNF agents have not yet been reported. Finally, the use of contemporary cytokine profiling platforms could provide very useful information regarding which patients will respond most favorably to anti-TNF therapies.
Blocking IL-12 and IL-23 as a therapy for autoimmune diseases
Psoriasis is an inflammatory disease characterized by the rapid growth of skin cells. Researchers have found that T cells become activated and produce cytokines that spur the growth of skin cells as well as inflammation. One such cytokine is IL-12, which acts to promote development of Th1 cells that in turn produce IFN-γ. IL-23 acts preferentially to promote development of Th17 cells that in turn produce a variety of pro-inflammatory cytokines, such as IL-6, IL-17, and IL-22.
Ustekinumab (Stelara) is a human monoclonal antibody that binds the p40 subunit of IL-12 and IL-23 and prevents these cytokines from binding to the IL-12Rβ1 receptor and subsequent signaling. The drug is marketed in Canada and Europe for moderate to severe plaque psoriasis and is currently under review by the FDA for use in the U.S., said Michael Elliott of Centocor Inc.
By blocking both IL-12 and IL-23, ustekinumab inhibits inflammatory cell infiltration, normalizes cytokine expression in the skin, reduces epidermal hyperplasia, and promotes the maintenance of normal skin dendritic cell populations. The drug does not appear to affect circulating Th1, Th2, Treg, or NK cell populations, although there may be a trend to reductions in circulating Th17 cells.
Ustekinumab may also be useful as a treatment for psoriatic arthritis, and Crohn's disease, although these are unapproved indications. However it did not show efficacy against multiple sclerosis (MS).
Interferon-β in autoimmune disease
One cytokine that is often very effective in treatment of MS is interferon-β, said Richard Ransohoff of the Cleveland Clinic Foundation. Treatment with recombinant human IFN-β is partially effective against MS but it is expensive, inconvenient, has many side effects, and doesn't work for every patient. Nevertheless until its discovery, there were very few treatments options for the disease.
Researchers would like to be able to predict which patients will respond to interferon therapy. To find predictive markers, Ransohoff and his colleagues evaluated gene expression profiles to see if individuals treated with IFN-β had varied responses to this cytokine. The researchers used microarrays of a set of interferon-stimulated genes (ISGs) to examine changes in gene expression levels following IFN-β treatment.
They found that neither the magnitude nor the stability of the biological response to IFN-β was responsible for the difference in responsiveness among patients. They concluded that the specific gene or combination of genes induced or repressed by the treatment must be responsible. Their group and others have recently identified a number of genes that are associated with MS, and they are currently exploring how these genes respond to IFN-β treatment.
Another team that is performing gene expression profiling to learn more about how cytokines influence diseases is that of Virginia Pascual of the Baylor Institute for Immunology Research. They are looking for gene signatures associated with Systemic Lupus Erythematosus (SLE) that can serve as biomarkers for diagnosis and assessment of lupus disease activity. The diagram above shows the regulation of interferon-α, which is implicated in inflammation and could be a target for SLE therapy.
IL-1 in autoinflammatory disease
Research in rare genetic diseases can help expand our understanding of inflammatory processes in more common diseases, explained Raphaela Goldbach-Mansky of the Translational Autoinflammatory Disease Section at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Three such rare diseases are collectively called cryopyrin-associated periodic syndromes (CAPS). Familial cold autoinflammatory syndrome (FCAS) involves cold-induced attacks of fever, neutrophilic urticaria, conjunctivitis, and joint pain, lasting 12 to 24 hours then resolving. Muckle Wells syndrome (MWS) is a more severe and persistent disease that is not cold-induced and involves fever, neutrophilic urticaria, joint pain, progressive hearing loss, and amyloidosis. The third disorder is neonatal onset multi-system inflammatory disease (NOMID), involving the same symptoms as well as bony overgrowth of the knees, organ damage, and mental retardation.
All three of these diseases appear to be mediated by the proinflammatory cytokine, IL-1. A recombinant human IL-1 receptor antagonist, approved in 2000 (anakinra, KineretTM, Amgen) for the treatment of rheumatoid arthritis, provides a potential treatment for these diseases as well. Blocking IL-1 using anakinra in patients with NOMID resulted in immediate resolution of the skin rash. Their symptoms returned when IL-1 inhibitors were withdrawn. In patients with NOMID, blocking IL-1 helped restore hearing and vision in some patients but had no effect in others. However, IL-1 inhibitors did not help prevent the growth of bony lesions in the knees. Early diagnosis and treatment with an IL-1 inhibitor such as anakinra can reduce and perhaps prevent the development of organ specific damage and disability.
IL-1β in autoinflammatory disease
IL-1β plays a role in several inflammatory diseases, including RA, CAPS, and gout, said Neil Stahl of Regeneron Pharmaceuticals. Rilonacept (Arcalyst, Regeneron) a drug that is approved for treating CAPS and now is in phase 3 trials for gout, is a receptor-Fc fusion protein that traps and removes IL-1. It is highly specific and has a very high affinity for IL-1β. Rilonacept and IL-1β form a complex that prevents the biological activity of the cytokine.
If the rate of rilonacept-IL-1β complex removal from plasma is known, then it may be possible to calculate how much IL-1β is being made in different disease states. Stahl and his colleagues found that IL-1β levels are highest in CAPS (FCAS) followed by gout and then RA. Normal healthy volunteers appear to have very low IL-1β synthesis.
The researchers concluded that studying IL-1β:Rilonacept complex levels may prove useful in identifying IL-1β-"driven" diseases and in identifying diseases that are more responsive to IL-1 inhibition. Regeneron scientists, including Allen Radin, are exploring the use of Rilonacept for the treatment of chronic gouty arthritis, a rare subset of gout that is resistant to traditional gout therapeutics.