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Cytokine Therapies
Novel Approaches for Clinical Indications
Cytokine Therapies
Novel Approaches for Clinical Indications
Organizers: Raymond Donnelly and Amy Rosenberg (U.S. Food and Drug Administration), Howard Young (National Cancer Institute)Presented by the U.S. Food and Drug Administration and the New York Academy of SciencesReported by Catherine Zandonella | Posted July 2, 2009 Overview
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.
Presented by:
 
Cytokines as Anti-Cancer Agents
Highlights
- 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.
Lessons learned
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.
Cytokines and Cytokine Antagonists for the Treatment of Autoimmune and Inflammatory Diseases
Highlights
- 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.
The progression of rheumatoid arthritis.
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.
Regulation of IFN-α
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.
Cryopyrin-associated periodic syndromes (CAPS).
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
Rilonacept traps IL-1 and prevents it from binding to cell surface receptors.
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.
Using Bioengineering and Nanotechnology to Improve the Bioactivity and Targeted Delivery of Cytokines
Highlights
- 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 ActoBiotics can deliver proteins in the gastrointestinal tract.
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
The dock-and-lock method uses a dimerization and docking domain module (DDD2) and an anchoring module (AD2) locked together by a disulfide bond.
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.
Open Questions
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?
Keynote Lecture
Cytokines as Targets for Anti-inflammatory Agents
Speaker: Larry W. Moreland, MD
University of Pittsburgh
Well over a decade ago the role of tumor necrosis factor (TNF) was first described in patients with rheumatoid arthritis (RA) when clinical benefit was demonstrated using either a monoclonal antibody or a soluble receptor fusion protein. In 2009 there are now 5 anti-TNF agents approved (or soon to be approved) by regulatory agencies for treating RA. Moreover, anti-TNF therapies have also shown to have remarkable efficacy in psoriasis, seronegative spondyloarthropathies (e.g. psoriatic arthritis and ankylosing spondylitis), and other immune-mediated inflammatory disorders.
Recent research attention has focused on the potential adverse events that can be seen with these therapies; an increase in opportunistic infections being the most clearly linked adverse event. Not all RA patients have a positive clinical response to these agents. Thus, efforts have focused on mechanisms of failure (primary or secondary) of the anti-TNF agents in RA. Identifying which RA patients will have a meaningful clinical response (improvement in outcomes measures such as ACR 20, DAS score, remission, etc.) when used as monotherapy, or in combination with other immunosuppressive agents remains a major research effort.
These anti-TNF therapies have revolutionized the clinician ability to make a significant impact in RA, a disease that has significant excess morbidity and mortality. A limiting factor in allowing more widespread use of these biological agents is their expense. Recent new anti-cytokine approaches include other cytokine targets (e.g. IL-6) as well as therapies that can inhibit multiple cytokines. Oral agents that inhibit cell signaling pathways, and thus the production of multiple cytokines are currently being developed.
Session I
Why and When Does IL-2 Therapy Work: IL-2 Administration Promotes Autophagy and Tumor Cell Survival While Enhancing Damage Associated Molecular Pattern Molecule Release Following Cell Mediated Cytolysis
Speaker: Michael T. Lotze, MD*
University of Pittsburgh Cancer Institute
Recent evidence has pointed to the role of autophagy in promoting tumor cell growth and aggressive behavior. Although the antitumor effects of IL-2 are in part mediated by secondary elaboration of IFNγ, this also induces autophagy and autoimmunity. Most antitumor therapies including cytolysis by immune effectors and/or chemotherapy have similar consequences of releasing damage associated molecular pattern molecules from tumor cells limited in their ability to apoptose. It is our hypothesis that: (a) means to limit DAMP release will require enhancement and measure of apoptosis in tumor cells subjected to immunotherapy and (b) if not possible to promote apoptosis that means to limit DAMP release or eliminate DAMPs and aerobically denature them represent additional strategies important in promoting tumor clearance and limiting tumor driven consumption. Murine studies of liver metastases therapy applying IL-2 alone or in conjunction with ethyl pyruvate, a metabolic active agent important in limiting HMGB1, results in antitumor activity. Our results lend support to the notion that autophagic survival of tumors requires cytolysis for ablation, DAMP release, and enhanced autophagy requiring novel strategies to promote clearance.
More than 50% of individuals present with metastatic disease and conventional chemotherapeutic strategies have been associated with poor response rates. Immunotherapy with IL-2 can induce remission, with >10 year recurrence free survival in 5–10% of patients with advanced melanoma or renal cell cancer. Some of the possible mechanisms include enhancing cytotoxic immune cell functions and reversal of T cell anergy, enabling delivery of immune cells and possibly serum components into tumor. IL-2 indirectly limits tumor escape mechanisms such as defective tumor cell expression of Class I/II molecules or expansion of regulatory T cells. Indirect effects on the tumor microenvironment include rather dramatic T cell infiltration. No clear phenotype or genotype of IL-2 responders distinguishing them from nonresponders has emerged in the last 25 years since IL-2 therapy was initiated. The disturbed homeostatic host/tumor interaction is reset in a small subset of patients allowing an antitumor response to recover or ensue.
*Coauthors: Antonio Romo de Vivar Chavez, Xiaoyan Liang, Michael DeVera, Norimasa Ito, and Herbert J. Zeh; University of Pittsburgh Cancer Institute.
Lessons from Interferon Gamma: From Excitement to Orphan Drug and Beyond
Speaker: Steven M. Holland, MD
National Institute of Health, Bethesda
Interferon gamma: why is its therapeutic niche so small?
The cloning of interferon gamma in 1982 was supposed to herald in a new age of biologic cancer control, rational manipulation of host immunity, and the regulation of fibrosis. Today, interferon gamma is only licensed for the prophylactic management of chronic granulomatous disease of childhood and malignant osteopetrosis. Trials in a variety of infections, such as leprosy, tuberculosis, and leishmaniasis showed promise. However, large labeling studies in drug resistant tuberculosis, nontuberculous mycobacterial infections, and pulmonary fibrosis have not yielded indications. In the process, the pathway of interferon gamma signaling, it receptors and their signal transducers, crucial for the control of intracellular infections and some cancers, have been elucidated. Basic mechanisms of interferon gamma activity, signaling, and pathologic states are informative and will be reviewed.
Use of Gene Shuffling Technology to Develop Novel IFN-a Molecules: Successes and Challenges
Speaker: Julian A. Symons, PhD
Roche Palo Alto LLC
The human type I interferons (IFN) comprise a family of four helix bundle cytokines encoded by 13 non-allelic IFN-alpha subtypes, one IFN-beta subtype and one IFN-omega subtype. Although all type I interferons are recognized by a single shared receptor comprised of two transmembrane subunits, IFNAR-1 and IFNAR-2, these cytokines have an unusually pleiotropic activity profile, including antiproliferative, antiviral and immunomodulatory activities and consequently this family of cytokines has found clinical application in cancer, chronic viral diseases and autoimmune diseases. Gene Shuffling is a general approach to genetic engineering that exploits natural diversity in gene families and has been used to evolve highly novel variants of enzymes, cytokines, antibodies, insect toxins, and viruses. Using this technology we have modified three major classes of IFN-mediated activities to yield evolved variants which exhibit an unprecedented increase in both absolute antiviral activity against a number of viruses and greater immunomodulatory activity. Interestingly, in contrast to the enhanced antiviral and immunomodulatory activity, these molecules demonstrated similar activity to IFN alpha-2a in a Daudi cell antiproliferative assay. This unusual ratio of antiviral/immunomodulatory: antiproliferative activity was mapped to a novel pseudogene motif in a putative IFNAR1 binding region of the molecules (Brideau-Andersen et al, Proc. Natl. Acad. Sci. (USA) 104, 8269, 2007). In this presentation, an analysis of the structure-function, receptor binding, signal transduction and gene expression properties of these molecules as well as the clinical experience with R7025, a pegylated gene shuffled IFN alpha molecule, will be presented.
Session II
Interleukin-7: A Potent Immunomodulatory Agent with the Potential for Clinical Application
Speaker: Crystal L. Mackall, MD*
Center for Cancer Research, National Cancer Institute, Bethesda
Interleukin-7 is a member of the gamma-c cytokine family and required for T cell development in humans and animal models have demonstrated that IL-7 is required for postthymic survival of mature naïve T cells. Studies in lymphopenic humans and animals have also demonstrated the supraphysiologic levels of IL-7 augment peripheral T cell cycling. We conducted first in human studies of rhIL7 in patients with recurrent cancer using E. coli produced rhIL7. The agent was well tolerated over the 14 day treatment regimen with minimal toxicity. Immune modulation was substantial with increases in both peripheral blood CD4+ and CD8+ T cell numbers which coincided with increases in lymphoid tissue mass by radiographic imaging. The effects of rhIL7 on peripheral T cells appear to primary result from enhanced peripheral cell cycling and likely enhanced survival, with lesser if any effects on thymopoiesis. Notably however, rhIL7 preferentially increased naïve T cells numbers and preferentially induced cycling of this subset, with lesser increases in regulatory T cells and in effector memory populations. This resulted in broadening of the T cell receptor repertoire. Given that rhIL7 has been shown to be an effective vaccine adjuvant in animal models, we propose that this agent could be used in a variety of clinical applications from immunization strategies, to adoptive immunotherapy to enhancing the effectiveness of antiviral therapies. Future Phase II studies in targeted clinical settings are needed to more fully assess the potential clinical role of this agent.
*Coauthors: Claude Sportes, Fran Hakim, Hua Zhang, Ronald E. Gress, and Crystal L. Mackall; Center for Cancer Research, National Cancer Institute, Bethesda.
Interleukin-21 has Broad Effects on Innate and Antigen Specific Immunity
Speaker: William E. Carson III, MD
Ohio State University, Columbus
IL-21 is produced by activated CD4+ T cells. The IL-21 receptor (R) shares the common receptor gamma-chain with IL-2, -4, -7, -9, and -15, is widely expressed on immune cells, and mediates a variety of effects depending on the cell type under study. One consistent property of IL-21 is its ability to enhance the proliferation, antigen-induced activation, clonal expansion, IFN-gamma production, and cytotoxicity of CD8+ T cells. In addition to its effects on CD4+ and CD8+ T cells, IL-21 has context-dependent effects on B cells (such as the ability to induce granzyme B), amplifies macrophage activation pathways, and inhibits the activation of myeloid dendritic cells. IL-21 promotes the maturation of murine NK cells and down-regu-lates the expression of NKG2D on human NK cells while increasing their expression of the NK activation receptors NKp30 and 2B4. Co-stimulation of NK cells with IL-21 and IL-15 and/or IL-18 is also an effective stimulus to IFN-gamma production. Importantly, IL-21 is able to mediate the regression of established tumors in a variety of murine models. Depending on the method of cytokine delivery (exogenous cytokine, plasmid DNA, or retroviral transduction of tumor cells) its mechanism of action has been variously attributed to NK cell cytolytic activity, perforin-mediated CD8+ T cell cytotoxicity, CD4+ T cell help, NKT cells, and the anti-angiogenic actions of IL-21-induced IFN-gamma. Phase I trials reveal that IL-21 is well-toler-ated and has clinical activity as a single-agent (4% response rate in metastatic cancer). We have found that the administration of IL-21 will lead to activation of FcR-bearing immune cells and enhance their ability to recognize and eliminate anti-body-coated tumor cells. Of note, our preliminary data indicate that the anti-tumor activity of IL-21 and therapeutic monoclonal antibodies such as trastuzumab is dependent on NK cell production of IFN-gamma.
Interferon Lambda as a Potential New Therapeutic for Hepatitis C
Speaker: Dennis M. Miller, PhD
ZymoGenetics, Inc., Seattle
Interferon lambda (IFN-λ) or Interleukin-29 is a member of the Type III interferon family. The Type III IFNs signal through a receptor complex that is distinct from the Type I and II IFNs, yet the biological activities of the Type III IFN are similar to the Type I IFNs, such as IFN-α. In order to evaluate potential therapeutic opportunity of IFN-λ, a number of preclinical studies were conducted, including studies of the receptor distribution pattern and relative potency of IFN-λ. Compared to the widely distributed receptors for IFN-a, the expression pattern for the receptor for IFN-λ is more cell-specific, primarily expressed on epithelial cells, including hepatocytes. A high degree of similarity was seen in the gene expression pattern induced by IFN-λ or IFN-α. Since one major therapeutic use of IFN-α is the treatment of patients infected with Hepatitis C virus, the potential for IFN-λ to induce anti-viral genes and inhibit Hepatitis C replication in vitro was explored. IFN-λ induced the production of antiviral genes in primary hepatocytes and cell lines, and produced a dose dependent inhibition of the Hepatitis C virus replication; however the relative potency compared to IFN-α was difficult to assess in these model systems due to variability within the models. Initial clinical trials in healthy volunteers and subjects with Hepatitis C have demonstrated clear evidence of biological activity, including anti-viral activity, of a PEGylated form of IFN-λ. Treatment of Hepatitis C patients with IFN-α is frequently complicated by the side effects these patients experience. The more cell-specific receptor expression for IFN-l was hypothesized to lead to fewer off target effects, such as hematological toxicities. The safety data from animal and initial clinical trials supports the concept that PEG-IFN-λ may have a more favorable safety profile than IFN-a based therapies, especially with regards to hematological toxicities. In summary, the preclinical and early clinical data support the concept that IFN-λ has the potential to be a new therapeutic agent for the treatment of patients infected with Hepatitis C.
Session III
Interferons as Anti-cancer Agents: Where from Here?
Speaker: Ernest C. Borden, MD
Cleveland Clinic, Taussig Cancer and Lerner Research Institutes, Cleveland
Interferons (IFNs), a family of approximately 20 induced proteins, with receptors on almost every cell phenotype, influence tumor emergence, progression, and clinical regressions. Cellular actions of IFN-stimulated genes (ISGs), of which there are more than 300 transcriptionally regulated, have helped understand host resistance to tumor emergence and also define cellular actions. Constitutive decreases in both IFNs and ISGs through both genetic and epigenetic mechanisms have been identified. For example, mutation of a gene in the IFN response pathway, RNASEL, increases prostate cancer risk. Several ISGs, such as TRAIL and fas, are critical for extrinsic apoptotic cascade activation; these can be counterbalanced in effect by the ISG G1P3. Other ISGs are a critical part of T cell and p-dendritic cell function.
Strategies to use and persistently activate these and other ISGs such as STAT1 are currently being pursued. These actions in addition to anti-angiogenic effects could be a partial basis for effectiveness of IFNs and/or inducers in suppressing tumor emergence in carcinogen-induced murine tumors; potentially an oral inducer could play a role in clinical chemoprevention. IFNs were the first proteins not previously available clinically produced by recombinant technology and were subsequently the first human biological modifiers receiving FDA approval; they have thus been an important regulatory and clinical guide for development of other cytokines. Many important questions remain however unanswered: What do the multiple isoforms of IFNs-α do? Which of the ISGs are most important for antitumor effects? What mechanisms cause the difficult clinical side effects of fatigue and anorexia? What causes innate resistance? Can effective oral inducers be identified? How do IFNs synergize in action with other modalities of cancer therapy? Answers will facilitate future advance not only for malignancies but also for other human disease.
Ernest C. Borden et al. 2007. Interferons at age 50: past, current, and future impact... Nat. Rev. Drug Discov. 6: 975-990.
Clinical and Immunologic Basis of Interferon Therapy in Melanoma
Speaker: Ahmad A. Tarhini, MD*
University of Pittsburgh Cancer Institute
In 2009, a predictably curative therapy for metastatic melanoma has yet to be identified, but we have begun to understand the immunosuppressive impact of melanoma upon the human host, and how melanoma evades immune response through the induction of tumor tolerance. Interferon α2b (IFN-α2b) at high dosage is critical to the reversal of signaling defects in T cells of melanoma patients and to the polarization of dendritic cells, and these immunoregulatory effects appear to be uniquely achieved with levels of IFNα only attainable in vivo using the high-dose regimen of IFN-α2b (HDI). Three US national cooperative group studies have evaluated the benefit of HDI as an adjuvant therapy for high-risk melanoma. All demonstrated significant and durable reductions in the frequency of relapse, while the first and third trials demonstrated significant improvements in the fractions of patients surviving compared with observation (E1684) or with GMK vaccine in E1994. A recent meta-analysis of individual patient data from all the available randomized trials evaluating adjuvant IFN therapy has not clarified the optimal dosage (high, intermediate or low) of IFN but demonstrated a statistically significant benefit for IFN in terms of both RFS and OS. Research of IFN-α therapy in melanoma is now focused on biomarkers that may have the capacity to predict the outcome of melanoma in the adjuvant setting. To evaluate the biomarkers of disease and host serological response individually, and in multiplex analyses. To identify prognostic markers of disease outcome and predictors of therapeutic response to HDI (and by extension, other immunotherapeutic agents such as IL-2 and anti-CTLA4 monoclonal antibodies).
*Coauthor: John M. Kirkwood, University of Pittsburgh Cancer Institute.
Session IV
Effect of PEGylation on the Activity of Cytokines
Speaker: Abraham Abuchowski, PhD
Prolong Pharmaceuticals
PEGylation has become the gold standard for protein drug delivery in the industry. Approved PEGylated drugs include enzymes (Adagen, Oncaspar), cytokines (PEG-Intron, PEGasys, Neulasta, Mircera) and receptor antagonists (Somavert, Macugen). Dozens more are in development.
The major benefit of PEGylation is extended circulating life. Depending on the extent and nature of the PEGylation, properties such as stability, resistance to proteolytic digestion, absorption kinetics and activity are affected.
This presentation will discuss the application and effect of the technology on various proteins.
The Nanoparticle Protein Corona — Opportunities and Challenges for Therapeutics
Speaker: Kenneth A. Dawson, PhD
Centre for BioNano Interactions, School of Chemistry and Chemical Biology, University College Dublin
The importance of understanding the interactions between nanoscale materials and living matter has now been appreciated by an extraordinarily range of stakeholders. It is certainly understood by researchers that as the potential to manipulate materials at nanometer scale grows this leads to the opportunity to stipulate and study specific interactions with cells, tissue, organs and whole organisms. The pace of advance is extraordinary. However industry, governments and society at large also now appreciate the opportunity and requirement for this arena of research. Not only does it open up new direction in nanomedicine and nanodiagnostics, but offers the chance to implement nanotechnology across all industry in a safe and responsible manner.
The underlying reasons are real and durable. Less than 100nm nanoparticles can enter cells, less that 40 nm they can enter cell nucleus, and less that 35 nm they can pass the blood brain barrier. These are fundamental length scales of biological relevance that will ensure that engineered nanoscience will impinge on biology and medicine for many decades.
Our core idea is that nanoparticles in a biologically relevant environment (cell media, plasma etc) draw to themselves a number of proteins and lipids that form a sort of dynamical 'corona' in slow exchange with the environment. The exchange times (of the 'hard corona') can be so slow that many early biological responses are already defined by these associated biomolecules. It is therefore these that define the biological identity of the nanoparticle, and it is important to learn their identity and more broadly to develop methods to assess them. Significant progress is being made in this arena, beyond the recent publications.
Having understood the nature of the expressed biomolecule the challenge is to study where the particles go (using imaging techniques) and assess their biological impact when they reach there. We present our recent studies of this type. We also comment on the possibility to apply novel techniques.
A key achievement of the field would then be to connect this biological identity (corona) to the observed biological impact. This has not been achieved yet, but progress is being made. An update is given.
We also note potential application of nanoparticles as delivery systems for cytokines. Within the talk we present some thoughts and suggestions for how this nanotechnology and in particular, the nanoparticle protein corona, can be used to 1) better target cytokines to the tissues of interest 2) prolong half life and 3) prevent immunogenicity.
Session V
The Use Of Actobiotics as a Novel Method for Cytokine Delivery
Speaker: Lothar Steidler, PhD
ActoGeniX NV, Zwijnaarde, Belgium
We have pioneered genetic modification of the dairy bacterium Lactococcus lactis for secretion of bioactive, regulatory proteins such as cytokines, trefoil factors and growth factors. In this we saw the concept of a novel class of therapeutics: genetically modified Lactococcus for active deliver of biologicals to the mucosa of the nose, intestine and mouth. We are developing L. lactis that produce the anti-inflammatory IL-10 (LLIL-10) for treatment of inflammatory bowel disease. In several mouse models of colitis (chronic DSS, IL10−/−, TNBS, CD4+CD45Rbhi transfer), oral LLIL-10 treatment resulted in a marked reduction of the pathology, both in prophylactic as well as in a therapeutic settings.
To preclude dissemination of genetically modified L. lactis, medical use requires an in-built environmental containment strategy. Thymidylate synthase (ThyA) is an essential enzyme in DNA metabolism, providing thymine and thymidine. Genetic exchange of the chromosomal thyA gene for the human IL-10 gene provides LLIL-10 that critically depend on the addition of thymidine or thymine. Both are very scarce, if not absent, in the environment and are only present at limiting concentrations in vivo.
In a phase 1 safety study, environmentally contained LLIL-10 were administered to severe Crohn's disease patients. The use of LLIL-10 in humans was shown to be safe, well tolerated and environmental containment was confirmed. Crohn's disease activity as well as C-reactive protein levels were clearly reduced in >50% of patients. By use of further improved LLIL-10, we are currently conducting a phase 2, multicenter, randomized, placebo controlled clinical trial in mild to moderate ulcerative colitis patients.
Heterogeneous, Longitudinally-Stable Molecular Signatures in Response to Interferon-β
Speaker: Richard M. Ransohoff, MD*
Neuroinflammation Research Center and Mellen Center for MS Treatment and Research, Cleveland Clinic
Interferons (IFNs) are widely used in therapy for viral, neoplastic and inflammatory disorders, but clinical response varies between patients. The molecular basis for
variability among patients is not known. The primary molecular response to IFN-β(IFN-β injections in treatment-naïve multiple sclerosis (MS) patients, initiating IFN-β
therapy was determined, using a customized cDNA macroarray with >150 interfer-on-stimulated genes (ISGs). Our results revealed inter-individual heterogeneity, both in the magnitude and nature of the molecular response to IFN-β injections. However, the molecular response was phenotypically stable over time for most (>80%) patients, as defined by a Pearson correlation coefficient >0.6 between fold induction for individual ISGs at baseline and 6 months. Longitudinally-stable and robust IFN-inducible gene expression was observed both in the clinical responders and
non-responders to IFN-β. Therefore, failure to express ISGs was not the sole determinant of treatment failure. Our data indicate that clinical response to IFN-β therapy for MS differs among patients because of quantitative or qualitative variability in the molecular response to the drug.
*Coauthors: M. R. Sandhya Rani1, Jar-chi Lee2, Yaomin Xu2, Jennifer Shrock1, Anupama Josyula1, Joerg Schlaak3, Richard A. Rudick4.
1 Neuroinflammation Research Center, Cleveland Clinic.
2 Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic.
3 University of Essen, Germany.
4 Mellen Center for MS treatment and Research, Cleveland Clinic.
The Role of IL-1 in Two Monogenic Autoinflammatory Diseases
Speaker: Raphaela Goldbach-Mansky, MD*
National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda
The proinflammatory cytokine, IL-1, has a role in a number of inflammatory conditions, however its pivotal contribution to the pathogenesis of human disease became evident with the discovery, that mutations in CIAS1/NLRP3 encoding cryopyrin, -the key component of a molecular complex (inflammasome) that leads to caspase-1 mediated activation of IL-1β, cause a disease spectrum recognized as cryopyrin associated periodic syndromes (CAPS). Untreated patients with the most severe, sporadic form of CAPS, neonatal-onset multisystem inflammatory disease (NOMID/ CINCA) have significant cognitive and physical disabilities and high mortality.
We are following a cohort of NOMID patients treated with escalating doses of IL-1 receptor antagonist up to 5mg/kg/day to achieve inflammatory remission. Three year outcome data in 20 NOMID patients suggest that the disabilities which include progressive hearing and vision loss, hydrocephalus and cerebral atrophy derive from IL-1β mediated inflammatory organ damage and that treatment with anakinra can halt progression of organ damage at 3 years.
Importantly, we recently identified a novel autoinflammatory disease, DIRA, deficiency of the IL-1 receptor antagonist, an autosomal recessive disorder caused by truncating mutations in or a homozygous genomic deletion including IL1RN. The absence of functional IL-1 receptor antagonist leads to systemic, pustular skin and bone inflammation not observed in NOMID.
NOMID and DIRA are two distinct, IL-1 dependent, autoinflammatory diseases. The pivotal role of IL-1β oversecretion in NOMID and uninhibited IL-1 signaling in DIRA can be demonstrated in clinical studies using IL-1 blockade. Both diseases are human models to study the contribution of IL-1 to organ specific inflammation and serve as paradigms to further our understanding of the pathogenesis of phenotypically similar diseases such as, psoriasis, Behcet's disease and chronic recurrent multifocal osteomyelitis (CRMO).
*Coauthors: Daniel L. Kastner and Ivona Aksentijevich (for the NOMID and DIRA study groups); National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda.
Clinical Use Of Type I Interferon and IL1b Antagonists in Rheumatic Diseases
Speaker: Virginia Pascual, MD*
Baylor Institute for Immunology Research, Dallas
Our studies in children with rheumatic diseases have led to the identification of two of the oldest cytokines, type I Interferon (IFN) and Interleukin 1 (IL-1), as important pathogenic players in Systemic Lupus Erythematosus (SLE) and Systemic onset Juvenile Arthritis (SoJIA) respectively. These findings were obtained by studying the transcriptional profiles of patient blood cells and by assessing the biological and transcriptional effect(s) of active patient sera on healthy blood cells. We also identified a signature which can be used to promptly diagnose SoJIA from other febrile conditions. Interferon-alpha blockade is currently being tested in patients with lupus. Pilot clinical trials using recombinant IL-1RA (Anakinra) have already shown remarkable clinical benefits in SoJIA patients refractory to other medications. New IL-1 inhibitors such as IL-1 Trap (high affinity inhibitor of IL-1 consisting of the Fc portion of human IgG1 and the extracellular domains of IL-1R1 and IL-1RAcP) are being tested in clinical trials, and neutralizing human monoclonal antibodies to IL-1b are also being developed. An important remaining challenge is to determine the cause of IL-1 dysregulation in SoJIA patients. Additionally, whether IL-1 is a universal mediator of SoJIA remains to be established. Large multicentric clinical trials with IL-1 blockers will help elucidate the heterogeneity of the disease. This, in conjunction with specific diagnostic tests, would allow the prompt initiation of effective therapies as soon as the first symptoms of inflammation appear.
*Coauthors: Florence Allantaz, Damien Chaussabel, and Jacques Banchereau; Baylor Institute for Immunology Research, Dallas.
Web Sites
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.
Interferon-Stimulated Gene Database
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.
Books
Holland JF, Frei E, eds. 2003. Cancer Medicine, 6th Edition. BC Decker, Hamilton, Ontario.
Holland SM, ed. 2001. Cytokine Therapeutics in Infectious Diseases. Lippincott Williams & Wilkins, Philadelphia.
Ransohoff RM, Benveniste EN. 2006. Cytokines and the CNS. CRC Press, London.
Journal Articles
Raymond P. Donnelly
Donnelly RP, Sheikh F, Kotenko SV, Dickensheets H. 2004. The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J. Leukoc. Biol. 76: 314-321.
Junttila IS, Mizukami K, Dickensheets H, et al. 2008. Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4R alpha, IL-13R alpha-1 and the common gamma chain regulates relative cytokine sensitivity. J. Exp. Med. 205: 2595-2608.
Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. 2003. Interferon-lambdas mediate anti-viral protection through a distinct class II cytokine receptor complex. Nat. Immunol. 4: 69-77.
Maher SG, Sheikh F, Scarzello AJ, et al. 2008. IFN-α and IFN-λ differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol. Ther. 7: 1109-1115.
Yoon SI, Logsdon NJ, Sheikh F, et al. 2006. Conformational changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and assembly of the signaling complex. J. Biol. Chem. 281: 35088-35096.
Michael T. Lotze
Lee JJ, Lotze MT. 2009. Molecular basis of metastasis. N. Engl. J. Med. 360: 1679.
Lotfi R, Schrezenmeier H, Lotze MT. 2009. Immunotherapy for cancer: promoting innate immunity. Front. Biosci. 14: 818-832.
Moschos SJ, Mandic M, Kirkwood JM, et al. 2008. Focus on FOCIS: interleukin 2 treatment associated autoimmunity. Clin. Immunol. 127: 123-129.
Romo de Vivar Chavez A, de Vera ME, Liang X, Lotze MT. 2009. The biology of interleukin-2 efficacy in the treatment of patients with renal cell carcinoma. Med. Oncol. 26 Suppl 1: 3-12.
Sabatino M., Kim-Schulze S, Panelli MC, et al. 2009. Serum vascular endothelial growth factor (VEGF) and fibronectin predicts clinical response to high-dose interleukin-2 (IL-2) therapy. J. Clin. Oncol. In press.
Steven M. Holland
Haerynck F, Holland SM, Rosenzweig SD, et al. 2008. Disseminated Mycobacterium avium infection in a patient with a novel mutation in the interleukin-12 receptor-beta1 chain. J. Pediatr. 153: 721-722.
Paulson ML, Freeman AF, Holland SM. 2008. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr. Opin. Allergy Clin. Immunol. 8: 527-533.
Julian A. Symons
Brideau-Andersen AD, Huang X, Sun SC, et al. 2007. Directed evolution of gene-shuffled IFN-alpha molecules with activity profiles tailored for treatment of chronic viral diseases. Proc. Natl. Acad. Sci. USA 104: 8269-8274.
Crystal T. Mackall
Capitini CM, Cooper LJ, Egeler RM, et al. 2009. Highlights of the First International "Immunotherapy in Pediatric Oncology: Progress and Challenges" Meeting. J. Pediatr. Hematol. Oncol. 31: 227-244.
Dean RM, Fry T, Mackall C, et al. 2008. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J. Clin. Oncol. 26: 5735-5741.
Guimond M, Veenstra RG, Grindler DJ, et al. 2009. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat. Immunol. 10: 149-157.
Sportès C, Hakim FT, Memon SA, et al. 2008. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J. Exp. Med. 205: 1701-1714.
William E. Carson III
Gowda A, Roda J, Hussain SR, et al. 2008. IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro. Blood 111: 4723-4730.
Mani A, Roda J, Young D, et al. 2008. A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab. Breast Cancer Res. Treat. Dec 3. [Epub ahead of print]
Raig ET, Jones NB, Varker KA, et al. 2008. VEGF secretion is inhibited by interferon-alpha in several melanoma cell lines. J. Interferon Cytokine Res. 28: 553-561.
Skak K, Kragh M, Hausman D, et al. 2008. Interleukin 21: combination strategies for cancer therapy. Nat. Rev. Drug Discov. 7: 231-240.
Zimmerer JM, Lesinski GB, Ruppert AS, et al. 2008. Gene expression profiling reveals similarities between the in vitro and in vivo responses of immune effector cells to IFN-alpha. Clin. Cancer Res. 14: 5900-5906.
Ernest C. Borden
Borden EC. 2007. Augmentation of effects of interferon-stimulated genes by reversal of epigenetic silencing: potential application to melanoma. Cytokine Growth Factor Rev. 18: 491-501.
Borden EC, Sen GC, Uze G, et al. 2007. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 6: 975-990.
Cheriyath V, Glaser KB, Waring JF, et al. 2007. G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells. J. Clin. Invest. 117: 3107-3117.
Taylor KL, Leaman DW, Grane R, et al. 2008. Identification of interferon-beta-stimulated genes that inhibit angiogenesis in vitro. J. Interferon Cytokine Res. 28: 733-740.
Ahmad A. Tarhini
Kirkwood JM, Tarhini AA. 2009. Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy. J. Clin. Oncol. Apr 13. [Epub ahead of print]
Kirkwood JM, Tawbi HA, Tarhini AA, Moschos SJ. 2009. Does pegylated interferon alpha-2b confer additional benefit in the adjuvant treatment of high-risk melanoma? Nat. Clin. Pract. Oncol. 6: 70-71.
Kirkwood JM, Tarhini AA, Panelli MC, et al. 2008. Next generation of immunotherapy for melanoma. J. Clin. Oncol. 26: 3445-3455.
Tarhini AA, Kirkwood JM, Gooding WE, et al. 2008. A phase 2 trial of sequential temozolomide chemotherapy followed by high-dose interleukin 2 immunotherapy for metastatic melanoma. Cancer 113: 1632-1640.
Tarhini AA, Stuckert J, Lee S, et al. 2008. Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients participating in Intergroup Trial ECOG 1694. J. Clin. Oncol. 27: 38-44.
Abraham Abuchowski
Abuchowski A, McCoy JR, Palczuk NC, et al. 1977. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J. Biol. Chem. 252: 3582-3586.
Kenneth A. Dawson / Anna Salvati
Dawson KA, Salvati A, Lynch I. 2009. Nanotoxicology: nanoparticles reconstruct lipids. Nat. Nanotechnol. 4: 84-85.
Larry W. Moreland
Kremer JM, Genant HK, Moreland LW, et al. 2008. Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum. 58: 953-963.
Mease PJ, Reich K; Alefacept in Psoriatic Arthritis Study Group. 2009. Alefacept with methotrexate for treatment of psoriatic arthritis: open-label extension of a randomized, double-blind, placebo-controlled study. J. Am. Acad. Dermatol. 60: 402-411.
Moreland LW, Curtis JR. 2008. Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. Semin. Arthritis Rheum. Nov 18. [Epub ahead of print]
Saag KG, Teng GG, Patkar NM, et al; American College of Rheumatology. 2008. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 59: 762-784.
Lothar Steidler
Frossard CP, Steidler L, Eigenmann PA. 2007. Oral administration of an IL-10-secreting Lactococcus lactis strain prevents food-induced IgE sensitization. J. Allergy Clin. Immunol. 119: 952-959.
Neirynck S, Steidler L. 2006. Delivery of therapeutic proteins through Lactococcus lactis. Biotechnol. Genet. Eng. Rev. 22: 253-266.
Steidler L, Rottiers P. 2006. Therapeutic drug delivery by genetically modified Lactococcus lactis. Ann. NY Acad Sci. 1072: 176-186.
Waeytens A, Ferdinande L, Neirynck S, et al. 2008. Paracellular entry of interleukin-10 producing Lactococcus lactis in inflamed intestinal mucosa in mice. Inflamm. Bowel Dis. 14: 471-479.
Richard Ransohoff
Rudick RA, Ransohoff RM. 2008. Biomarkers for interferon response in MS: are we there yet? Neurology 70: 1069-1070.
Raphaela Goldbach-Mansky
Glaser RL, Goldbach-Mansky R. 2008. The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies. Curr. Allergy Asthma Rep. 8: 288-298.
Goldbach-Mansky R, Dailey NJ, Canna SW,et al. 2006. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N. Engl. J. Med. 355: 581-592.
Goldbach-Mansky R, Shroff SD, Wilson M, et al. 2008. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 58: 2432-2442.
Ryan JG, Goldbach-Mansky R. 2008. The spectrum of autoinflammatory diseases: recent bench to bedside observations. Curr. Opin. Rheumatol. 20: 66-75.
M. Virginia Pascual
Bosca I, Coret F, Valero C, et al. 2008. Effect of relapses over early progression of disability in multiple sclerosis patients treated with beta-interferon. Mult. Scler. 14: 636-639.
Pascual V, Allantaz F, Patel P, et al. 2008. How the study of children with rheumatic diseases identified interferon-alpha and interleukin-1 as novel therapeutic targets. Immunol. Rev. 223: 39-59.
Rönnblom L, Pascual V. 2008. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 17: 394-399.
Neil Stahl
Hoffman HM, Throne ML, Amar NJ, et al. 2008. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58: 2443-2452.
Allen Radin
Radin AI, Kim HT, Grant BW, et al.; Eastern Cooperative Oncology Group. 2003. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group. Cancer 98: 100-109.
Radin AI, Buckley P, Duffy TP. 1991. Interferon therapy for agnogenic myeloid metaplasia complicated by immune hemolytic anemia. Hematol. Pathol. 5: 83-88.
Howard A. Young
Hodge DL, Yang J, Buschman MD, et al. 2009. IL-l5 enhances proteasomal degradation of Bid in normal lymphocytes: implications for large granular lymphocyte leukemias. Cancer Res. 69: 3986-3994.
Rodriguez-Galan MC, Reynolds D, Graciela Correa S, et al. 2009. Co-expression of IL-18 strongly attenuates IL-12-induced systemic toxicity through a rapid induction of IL-10 without affecting its anti-tumor capacity. J. Immunol. in press (July 1).
Young HA, Ortaldo J 2006. Cytokines as critical co-stimulatory molecules in modulating the immune response of natural killer cells. Cell Res. 16: 20-24.
Organizers
Raymond P. Donnelly, PhD
Food and Drug Administration
e-mail | web site | publications
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
Food and Drug Administration
e-mail | web site | publications
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
National Cancer Institute
e-mail | web site | publications
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
The New York Academy of Sciences
e-mail | web site
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.
Speakers
Abraham Abuchowski, PhD
Prolong Pharmaceuticals
email | web site | publications
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
Cleveland Clinic and Taussig Cancer Institute
e-mail | web site | publications
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
Food and Drug Administration
e-mail | web site | publications
ShaAvhree Buckman is the director of the Center for Drug Evaluation and Research at the Food and Drug Administration.
William E. Carson, III, MD
Ohio State University, Columbus
e-mail | web site | publications
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
Immunomedics
e-mail | publications
Kathleen Clouse, PhD
FDA
e-mail | web site | publications
Kenneth A. Dawson, PhD
University College Dublin
e-mail | web site | publications
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
Centocor
e-mail
Raphaela Goldbach-Mansky, MD
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH
e-mail | web site | publications
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
National Institute of Allergy and Infectious Diseases, NIH
e-mail | web site | publications
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
Food and Drug Administration
e-mail | web site | publications
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
University of Pittsburgh Schools of the Health Sciences
e-mail | web site | publications
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
ZymoGenetics Inc.
e-mail | publications
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
University of Pittsburgh Medical Center
e-mail | web site | publications
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
The Journal of Clinical Investigation
e-mail | web site | publications
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
Baylor University
e-mail | web site | publications
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
Regeneron Pharmaceuticals
e-mail
Richard M. Ransohoff, MD
Lerner Research Institute; Case Western Reserve University
e-mail | web site | publications
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
Weill-Cornell Medical College; New York Presbyterian Medical Center
e-mail | web site | publications
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
Regeneron Pharmaceuticals
e-mail | web site | publications
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
ActoGeniX NV; Ghent University, Belgium
e-mail | web site | publications
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
Roche Palo Alto LLC
e-mail | web site | publications
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
publications
Ahmad Tarhini is a senior hematology/oncology fellow at the University of Pittsburgh Cancer Institute.
Daniela Verthelyi, MD, PhD
FDA
e-mail | web site | publications
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
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.
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