eBriefing

Advances in Immunomodulation: The 2014 Ross Prize In Molecular Medicine

Advances in Immunomodulation
Reported by
Hema Bashyam

Posted August 12, 2014

Presented By

Feinstein Institute for Medical Research, Molecular Medicine, and the New York Academy of Sciences

Overview

The Feinstein Institute for Medical Research established the Ross Prize in Molecular Medicine in 2013 in conjunction with its peer-reviewed open-access journal Molecular Medicine. The prize recognizes mid-career biomedical scientists whose discoveries have changed the way medicine is practiced, by advancing our understanding of human disease pathogenesis and/or the translation of research discoveries into treatments, and whose work holds promise for future contributions to molecular medicine.

On June 9, 2014, the Feinstein Institute for Medical Research and Molecular Medicine presented the 2014 Ross Prize in Molecular Medicine at New York Academy of Sciences. The symposium, titled Advances in Immunomodulation, honored this year's awardee, John J. O'Shea, scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the National Institutes of Health (NIH). The award ceremony was followed by presentations by O'Shea and other immunologists, who described discoveries that have enabled therapeutic targeting of cytokine signaling molecules in autoimmune and inflammatory diseases and of immune checkpoint modulators such as CTLA4 in cancer.


The 2014 Ross Prize in Molecular Medicine was awarded to Dr. John J. O'Shea for his discoveries in immunology and cytokine biology.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
James P. Allison, PhD (University of Texas MD Anderson Cancer Center)
Charles A. Dinarello, MD (University of Colorado–Denver)
John J. O'Shea, MD (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH)


This symposium was made possible with support from

  • Molecular Medicine
  • Feinstein Institute

Cytokine Signaling: Basic and Applied


John J. O'Shea (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH)
  • 00:01
    1. Introduction
  • 03:53
    2. Researching Jak3; Developing Jak inhibitors
  • 13:30
    3. Jakinibs and rare interferonopathies; Current challenges
  • 20:14
    4. Researching CD4 T cells; Cell identity; Enhancers and superenhancers
  • 27:11
    5. T cell stretchenhancers; Bach2 function; Effects of therapeutic agents
  • 34:00
    6. Summary, acknowledgements, and conclusio

Targeting Immune Checkpoints in Cancer Therapy


James P. Allison (University of Texas MD Anderson Cancer Center)
  • 00:01
    1. Introduction and history
  • 05:24
    2. Anti-CTLA-4 studies; Ipilimumab and melanoma
  • 12:55
    3. Metastatic melanoma drug trials and results
  • 17:10
    4. Combinations to increase efficacy; PD-1 studies; Additional costimulatory pathways
  • 24:00
    5. Rethinking clinical trial design; ICOS and IVAX studies
  • 32:48
    6. Summary and conclusio

Blocking IL-1β or IL-1α in a Broad Spectrum of Inflammatory Diseases


Charles A. Dinarello (University of Colorado–Denver)
  • 00:01
    1. Introduction; IL-1 history and overview
  • 07:55
    2. Anakinra studies; Behcet's disease and type 2 diabetes studies
  • 16:15
    3. Post-myocardial infarction remodeling; The issue of IL-1-alpha
  • 23:23
    4. Interpretations; Acknowledgements and conclusio

Journal Articles

Cytokine signaling: basic to applied research

Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003;302:875-8.

Johnston JA, Kawamura M, Kirken RA, et al. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994;370(6485):151-3.

O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368:161-70.

O'Shea JJ, Kanno Y, Chan AC. In search of magic bullets: the golden age of immunotherapeutics. Cell. 2014;157:227-40.

Roychoudhuri R, Hirahara K, Mousavi K, et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature. 2013;498:506-10.

Russell SM, Tayebi N, Nakajima H, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995;270(5237):797-800.

Vahedi G, Takahashi H, Nakayamada S, et al. STATs shape the active enhancer landscape of T cell populations. Cell. 2012;151:981-93.

Targeting immune checkpoints in cancer therapy

Fan X, Quezada SA, Sepulveda MA, et al. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med. 2014;211(4):715-25.

Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134-44.

Krummel MF, Allison JP. Pillars article: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. The journal of experimental medicine. 1995. 182:459-465. J Immunol. 2011;187(7):3459-65.

Ng Tang D, Shen Y, Sun J, et al. Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer Immunol Res. 2013;1(4):229-34.

Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300-9.

Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013;1291:1-13.

Blocking IL-1β or IL-1α in a broad spectrum of inflammatory diseases

Dinarello CA. Interleukin-1α neutralisation in patients with cancer. Lancet Oncol. 2014;15(6):552-3.

Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2010;17(4):314-21.

Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633-52.

Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469-84.

Hong DS, Hui D, Bruera E, et al. MABp1, a first-in-class true human antibody targeting interleukin-1α in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 2014;15(6):656-66.

Raffeiner B, Botsios C, Dinarello C, et al. Adult-onset Still's disease with myocarditis successfully treated with the interleukin-1 receptor antagonist anakinra. Joint Bone Spine. 2011;78(1):100-1.

Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162(4):597-605.

Speakers

James P. Allison, PhD

University of Texas MD Anderson Cancer Center
website | publications

James P. Allison is a professor of immunology, executive director of the Immunology Platform, and deputy director of the David H. Koch Center for Applied Research of Genitourinary Cancers at the University of Texas MD Anderson Cancer Center. He is also a Howard Hughes Medical Institute investigator. Allison received a PhD in biological sciences from the University of Texas at Austin and completed postgraduate training in molecular immunology at Scripps Clinic and Research Foundation. His translational studies showing that antibody-mediated blockade of CTLA4 coinhibitory function could enhance antitumor immunity and result in tumor rejection in mice prompted clinical development of ipilimumab, a CTLA4-blocking monoclonal antibody. Ipilimumab is the first drug of its kind to show survival benefit in melanoma patients and was approved by the FDA in 2011 as a standard-of-care therapy for late-stage melanoma patients. Allison's concept of antibody-mediated blockade of immunologic checkpoints as cancer therapy has opened a new field of immunotherapy, with second-generation agents, such as anti-PD1 antibodies, under investigation in preclinical and clinical settings as treatments for cancer.

Charles A. Dinarello, MD

University of Colorado–Denver
website | publications

Charles A. Dinarello is a professor of medicine and immunology at the University of Colorado School of Medicine and a professor of experimental medicine at Radboud University in the Netherlands. He was previously a professor at Tufts University. Dinarello received his MD from Yale University and completed clinical training at Massachusetts General Hospital. He was the first to purify interleukin-1 (IL-1), and his research has focused on on inflammatory cytokines, particularly interleukin-1, the interleukin-1 family, and related cytokines. He is a member of the Board of Governors of the Weizmann Institute and Ben-Gurion University in Israel. He is former vice president of the American Society of Clinical Investigation and president of the International Cytokine Society. He has received honorary degrees from the University of Marseille in France, the Weizmann Institute in Israel, the University of Frankfurt in Germany, Radboud University, Trinity College in Ireland, Roosevelt University, and Albany Medical College. In November 2013, Dinarello received the Lifetime Achievement Award of the Eicosanoid Foundation for his pioneering studies on the role of lipids in cytokine-mediated inflammation.

John J. O'Shea, MD

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH
website | publications

John J. O'Shea received his MD from the University of Cincinnati and completed a residency in internal medicine at the State University of New York Upstate Medical University followed by training at the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health. He is director of the Intramural Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, and an adjunct professor of pathology at the University of Pennsylvania. His research focuses on cytokine signal transduction, dissecting the role of JAK and STAT family transcription in immunoregulation. His group cloned the tyrosine kinase JAK3 and demonstrated its role in the pathogenesis of severe combined immunodeficiency. It also identified the role of STAT3 in regulating T-cell cytokine production in Job's syndrome. O'Shea was awarded two U.S. Patents related to his work on Janus family kinases and identification of immune modulators. More recently his group has focused on STATs in epigenetic regulation of T-cell differentiation. In addition to the Ross Prize and three NIH Director's Awards, O'Shea has received the U.S. Public Health Service Physician Researcher of the Year Award, the Irish Immunology Public Lecture Award, the Arthritis Foundation's Howley Prize, and the Daniel Drake Award. He is an elected member of the American Association of Physicians (AAP) and a fellow of the American Association for the Advancement of Science (AAAS). He serves on the editorial boards of Immunity and the Journal of Experimental Medicine.


Hema Bashyam

Hema Bashyam holds a PhD in immunology and virology from the University of Massachusetts Medical School for her study of human immune responses to secondary dengue virus infections. She enjoys writing about basic research in creative, compelling ways for a diverse audience that includes scientists, clinicians, and lay readers.

Sponsors

This symposium was made possible with support from

  • Molecular Medicine
  • Feinstein Institute

The Ross Prize

The Ross Prize in Molecular Medicine is awarded by an advisory committee of six members representing the Feinstein Institute for Medical Research (Betty Diamond and Peter Gregersen), the journal Molecular Medicine (Kevin Tracey and Christopher Czura), and the Karolinska Institute (Lars Klareskog and Klas Kärre).

During a brief introduction of the prize, Tracey explained that the committee selects an awardee on the basis of a strong track record of inspired discovery; perseverance and follow-through, even after setbacks; and, perhaps most importantly, success translating research discoveries into treatments. The winner is awarded a $50 000 honorarium made possible by Feinstein Institute board members Robin and Jack Ross.

Opening the black box of immunology

In his introductory remarks, Gregersen described John O'Shea as achieving all three milestones while maintaining a commitment to mentoring young scientists, much like the first prize laureate, Dan Littman, who was in the audience. Gregersen cited a recent review by O'Shea, published in Cell, in which O'Shea notes that immunology was once a black box that could offer physicians only blunt tools to treat inflammatory and autoimmune diseases.

Over the past 40 years, however, innovations in molecular biology and genome sequencing have allowed immunologists to break open the black box and make sense of the "wires and parts" jumbled within. The discovery of cytokines and related molecules helped assemble a functional blueprint of the immune system that has been used to target individual molecules for therapeutic benefit in diseases like rheumatoid arthritis (RA) and cancer.

Cytokines are small proteins produced by immune cells such as T cells, B cells, and macrophages and by nonimmune cells such as endothelial cells. Cytokines modulate the immune system by binding to cell surface receptors and initiating intracellular signaling pathways that control gene activation. Cytokine activity is crucial for the initiation and balance of innate and adaptive immune responses and the maturation and expansion of various cell populations. Cytokines thus play an important role in developmental processes and host immune responses.

Cytokine dysregulation can have pathological consequences ranging from immunodeficiencies to cancer. Over the last three decades, O'Shea's efforts to understand cytokine signaling and regulation have helped uncover the genetic and molecular basis of primary immunodeficiencies and autoinflammatory disorders such as RA. The Ross Prize recognizes his leadership in this field as well as his pioneering role in the discovery and application of a new class of immunosuppressive drugs called Janus kinase inhibitors (Jakinibs), the first of which was approved for the treatment of RA in 2003.

The JAK/STAT pathway: conveying environmental cues to the genome

Structural analysis of the 200 cytokines has divided them into several major families. Cytokines that bind the type I and type II cytokine receptors are distinct in their requirement to recruit Janus kinases (JAKs) for intracellular signaling. Unlike other receptors, the type I and II receptors do not encode their own kinase domains that can undergo phosphorylation to activate downstream signals. Instead, the 60 or so receptors belonging to these two types rely on JAKs, which they recruit upon cytokine binding.

Specific receptors pair with specific JAKs, and the activated JAKs in turn catalyze the phosphorylation of the cytokine receptor chains, creating docking sites for signaling molecules such as DNA binding proteins in the signal transducer and activator of transcription (STAT) family. STATs are another important JAK substrate, which when phosphorylated by JAKs translocate to the nucleus to regulate gene expression.

O'Shea's earliest work to understand how cytokine signaling drives T-cell activation resulted in a series of landmark papers between 1994 and 1996. A Nature paper described how a recently discovered member of the JAK family, JAK3, mediates T-cell activation driven by γ-chain family cytokines such as interleukin-2 (IL-2). O'Shea established a connection between this finding and a clinical phenotype, showing in a Science paper that defects in the JAK3 signaling pathway play a crucial role in severe combined immunodeficiency (SCID), in which lack of a functional immune system makes patients extremely vulnerable to infectious diseases.

Another line of investigation looked at how the JAK/STAT pathway affects the cellular genomes of T cells and triggers changes in genomic organization that underlie differentiation—the process by which naïve T cells mature into distinct T-cell functional subsets or lineages.

The realization by O'Shea and others that T-cell lineage is flexible, determined by signals from other cells, and therefore subject to manipulation for therapeutic benefit led to studies that explored whether inhibiting cytokine signaling could alleviate RA and other inflammatory disorders. There are now three FDA-approved JAK inhibitors in use: ruxolitinib for a trio of rare myeloproliferative disorders, tofacitinib for RA, and oclacitinib for dermatitis in canines. O'Shea elaborated on these topics in his lecture after the award presentation.

Speaker:
John J. O'Shea, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH

Highlights

  • The model describing differentiation of naïve CD4+ T cells into Th1 and Th2 cell lineages, a process driven by the selective expression of transcription factors, has become complex as researchers find out more about T-cell heterogeneity and plasticity; even mature cells can differentiate into a different lineage if the driving transcription factor is lost.
  • The parts of the genome that do not code for proteins are rich in enhancer, or switch, sequences that regulate the genome and define a cell's identity and function. Th1 and Th2 cells have 20 000 active enhancers concentrated within a small genomic region, of which 10 000 are shared between the two lineages and none are shared with other lineages.
  • Stretch or super enhancers—longer sequences—are critical coordinators of cell specificity in T cells. These regions are enriched for genes that code for cytokines and their receptors and are controlled by a master transcription factor called BACH2.

JAK inhibitors as therapeutics

Over the past three decades, John J. O'Shea of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has worked to understand cytokine signaling and regulation, helping uncover the genetic and molecular basis of primary immunodeficiencies and autoinflammatory disorders such as RA. Genome-wide association studies pinpointed several single nucleotide polymorphisms that confer genetic susceptibility to autoimmune diseases in genes encoding type I and II cytokine receptors and JAK/STAT members. Polymorphisms in IL12B, JAK2, and STAT3, for instance, are associated with inflammatory bowel disease (IBD) and psoriasis; polymorphisms in STAT4, with RA, systemic lupus erythematosus, and Sjogren's syndrome. These links between cytokine signaling and autoimmune diseases, combined with O'Shea's earlier work showing a connection between SCID and the absence of JAK/STAT signaling, suggested drugs that inactivate JAKs could be powerful immunosuppressants.

Drugs that block JAKs function as immunosuppressants by blocking cytokine signaling that switches on immune response genes. (Image courtesy of John J. O'Shea)

O'Shea sought to determine whether cytokine signaling could be selectively, safely, and effectively targeted. In 2003, with colleagues from Pfizer, he showed that it can be, with a first-generation JAK3 inhibitor called tofacitinib for the treatment of RA. This drug is now known to have the same efficacy as biologic agents used to treat the disease, and it works in patients who are refractory to the biologics.

Although not designed to do so, first-generation JAK3 inhibitors also show inhibitory activity toward JAK1 and JAK2, and therefore inhibit a broad range of cytokines. O'Shea speculated that the efficacy of these drugs could be explained by their activity against cytokines that activate both adaptive and innate arms of the immune system.

There are now 16 JAK inhibitors in use and in development. The newer inhibitors are designed to be more selective, targeting only one JAK isoform. But whether these drugs will be as effective as, and safer than, their predecessors is unknown. There is a dearth of information about how these drugs work; researchers are investigating which cytokines the drugs inhibit in different cell types and diseases. Given the extraordinary heterogeneity of the immune system, particularly the T-cell arm, O'Shea is particularly interested in exploring the exciting potential to expand the use of these drugs to multiple diseases.

Drivers of T-cell plasticity

The initial simple model of differentiation of naïve CD4+ T cells into Th1 and Th2 cell lineages, aided by master transcription factors that drive stereotypic gene expression, has become a complicated model that highlights T-cell heterogeneity and plasticity. CD4+ T cells, previously thought to be different from CD8+ T cells, can lose their "CD4ness" and become cytotoxic CD8+ T cells if the function of the transcription factor ThPok is lost.

The early simple model of T-cell differentiation has evolved into a complicated, messy picture that highlights lineage flexibility. (Image courtesy of John J. O'Shea)

In a bid to understand the rules that govern this complexity and identify the drivers of T-cell plasticity, O'Shea's group turned to the genome, investigating short stretches of DNA known as gene enhancers, or switches, that are sometimes bound with proteins to activate or silence gene transcription.

It is now known that 98% of the genome is not composed of genes but rather of so-called junk DNA; 80% of this junk DNA includes enhancer regions that regulate the genome and define the cell's identity and function. O'Shea's group defined these enhancers in CD4+ T cells by analyzing histone modifications—post-translational additions of chemical groups such as methyl and acetyl molecules to histone proteins, the chief components of chromatin that package DNA in the nucleus.

Mapping the enhancer landscape of CD4+ T cells

In a 2012 paper in Cell, O'Shea's group showed that active enhancers are concentrated within a small region of the genome in Th1 and Th2 cells. These cell types have 20 000 enhancers, of which 10 000 are shared between the two lineages and none are shared with other lineages. The paper also revealed a major role for STAT proteins in maintaining and shaping the enhancer landscape in these immune cells in response to environmental cues.

Cytokines are the major extracellular cues dictating T cell fate, acting mainly by activating STATs and their translocation to chromatin. By comparing the enhancer signatures of wild-type and STAT-deficient cells, O'Shea showed that the binding of STATs to enhancers reshapes the gene expression pattern in cells by creating new sites where other master regulators or transcription factors can bind.

Other groups, notably led by Francis S. Collins at the NIH and Richard A. Young at MIT, have mapped the enhancer landscapes of embryonic cells and identified about 10 000 enhancers and so-called stretch or super enhancers (SEs), which are 3–4 times longer. These studies also revealed that SEs are often tissue-specific and overlap with gene control regions, a sign that they are hotbeds of regulatory control in the chromatin that attract other regulatory elements such as transcriptional activators and repressors.

In another important finding, O'Shea's group and others demonstrated that the genomic neighborhoods where SEs are found are enriched for (heavily populated by) cell-specific genes, suggesting a role in specifying cell identity. In addition, disease-related genetic variant sequences are enriched in SEs compared to regular enhancers. Together, these findings have implicated SEs as critical coordinators of cell specificity and showed that sequence variation in SEs affects risk for common human diseases.

BACH2: controller of enhancers

O'Shea's group recently found that the dominant class of genes exhibiting SEs in T cells encodes cytokines and cytokine receptors. Specifically, in all three lineages of CD4+ T cells (Th1, Th2, and Th17), SEs are present in the highest numbers in BACH2, which codes a transcription factor that represses the cells' effector functions (such as cytokine production) and maintains T-cell homeostasis.

Other studies had linked polymorphisms in BACH2 to celiac disease, IBD, asthma, RA, and other autoimmune diseases. The critical role of BACH2 protein in immunity was confirmed when the scientists found that mice deficient in BACH2 suffer lethal autoimmunity and that BACH2 is required for the formation of T-regulatory (Treg) cells, which shut off or dampen immune responses. The latest evidence from O'Shea's lab has pegged BACH2 as the champion, or guardian, transcription factor that controls most SEs in T cells.

O'Shea's work recently revealed that JAK-inhibiting drugs such as tofacitinib can selectively regulate RA-associated genes that have the SE architecture. The finding that JAK inhibitors can preferentially control SEs associated with disease genes sets that stage for studies that can match JAK inhibitors with specific diseases.

Speaker:
James P. Allison, University of Texas MD Anderson Cancer Center

Highlights

  • Antibodies against CTLA4 ablate tumor growth in mouse models by increasing the infiltration of effector CD4+ and CD8+ T cells, thereby increasing the ratio of effector to suppressor T cells within the tumor.
  • The efficacy of CTLA4-blocking antibody ipilimumab, which has been approved for the treatment of melanoma, can be increased by combining it with other agents that target other immune checkpoint molecules such as PD-1 and ICOS.

Immunotherapy basics

Three features of the immune system make it uniquely effective in treating cancer: specificity, conferred by T cells that target MHC-presented peptides, generated by missense mutations and translocations that result from cancer's genomic instability; memory, from long-lived T cells generated in response to cancer; and adaptability, which makes the system a worthy adversary to mutable, adaptable cancer.

Insights that led to the immunotherapies in use today date to the mid-1990s, when James P. Allison and colleagues at the University of Texas MD Anderson Cancer Center discovered the relationship between T-cell receptors and the costimulatory molecules CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Signals from the T-cell receptor (upon binding peptide–MHC) and costimulating signals from CD28 (upon binding B71/2 ligands) are first essential for T cells to be activated and gain effector functions. Next, CTLA4, a homologue of CD28, is upregulated and binds to the same B71/2 ligands with greater affinity, shutting down the T-cell response.

Turning off the "off" signal in tumor-attacking T cells

After finding that the "on" signal for T cells is hardwired to a delayed "off" signal, researchers developed CTLA4-blocking antibodies as therapies to increase the immune response against tumors. Early experiments from Allison's lab showed that colon carcinoma transplanted into mice shrank within a month of injection with anti-CTLA4 antibodies, resulting in a sustained cure. Allison found this treatment approach exciting because it relies on jumpstarting the immune system—the biology of the cancer cell is irrelevant—and because it can be used either as monotherapy or in combination with other therapies that stimulate immunity, such as vaccines.

This theory was borne out when his group showed anti-CTLA4 antibodies to ablate tumor growth in several mouse cancer models and to work in synergy with tumor cell vaccines to eradicate melanoma. The latter approach works by increasing the infiltration of CD4+ effector and CD8+ memory T cells into tumors, activating the tumor vasculature to increase the ratio of effector T cells to immunosuppressive Treg cells in the tumor.

Fully human anti-CTLA4 antibodies received FDA approval in 2011 for first- and second-line therapies for melanoma. The treatment has been used in more than 35 000 patients under the commercial name Yervoy (ipilimumab). Objective tumor responses to this therapy, now approved in more than 40 countries, have been observed in melanoma, prostate, ovarian, kidney, and lung cancers.

Measurements of ipilimumab's therapeutic efficacy have not been without controversy. According to the World Health Organization (WHO) RECIST criteria for measuring tumor response, a positive response is defined by a greater than 50% shrinkage of tumor mass, an absence of new tumors, and a lack of growth in existing tumors. The response to ipilimumab, however, is characterized by an initial progression in tumors (increase in size of existing tumors and new tumor growth) before they begin to regress; the guidelines do not make an allowance for such a phenomenon, recommending that treatment be stopped if tumor growth is observed. Thus, by the WHO standards, Allison's experiments, which cured 100% of mice, would be considered failures.

Nonetheless, a recent pooled analysis of ipilimumab, which included 12 trials (n = 4846) for metastatic melanoma in patients treated under expanded access protocols (EAP), or compassionate use programs, confirmed the long-term survival benefit of this therapy, with a median overall survival (OS) of 9.5 months. Importantly, the survival rate plateaued from year 3 to year 10, independent of line of therapy, ipilimumab dose, or maintenance therapy, indicating that these were durable responses that lasted more than a decade. Based on this study, the 3-year OS rate of 21% is considered a benchmark for future therapies for this difficult-to-treat disease.

A large trial of ipilimumab in metastatic melanoma patients has confirmed the long-term survival benefit of this therapy, showing a median overall survival of 9.5 months and a 3-year OS rate of 21%, a new benchmark for future therapies. (Image courtesy of James P. Allison)


 

Combining anti-CTLA4 and anti-PD-1 therapies: a double knockout against cancer

Allison has since turned to deciphering the mechanisms of anti-CTLA4 therapy in cancer. He is also investigating how to increase the response rate by combining this therapy with conventional therapies, vaccines, and perhaps most exciting, antibodies against other checkpoint molecules like programmed cell death 1 (PD-1, or PDCD1), which dampens the immune response by blocking T-cell receptor signaling. This mechanism is different from that of CTLA4, which interferes with costimulation.

Treatment of melanoma patients with an anti-PD-1 antibody monotherapy (nivolumab) produced an objective response rate (ORR) of 30%; but a phase I trial that combined ipilimumab and nivolumab in advanced melanoma patients showed an ORR of 50% and evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) in 65% of patients. A follow-up study that included responsive patients and an extended cohort, presented at the American Society of Clinical Oncology's 2014 annual meeting, found a 1-year overall survival rate of 85% and 2-year overall survival rate of 79%.

Buoyed by these results, Allison is focusing on other checkpoint molecules that can be targeted in combination with CTLA4. A good candidate is ICOS, a costimulatory molecule that is induced in patients treated with ipilimumab. His team found an association between the sustained increase in ICOS+ T cells following ipilimumab therapy and a survival benefit in melanoma patients. It recently demonstrated that the efficacy of anti-CTLA4 therapy can be enhanced by first treating patients with a peptide vaccine to stimulate the ICOS pathways. The simultaneous action of both therapies increased cytotoxic T cells and IFN-γ- and TNF-α-producing cells in tumors while decreasing Treg cells. With such advances, Allison opined that the field is well on its way to markedly improving durable responses and survival in cancer with combination immunotherapy.

Wild-type mice with melanoma have a much higher survival rate when treated with a combination of ICOS-stimulating vaccine and anti-CTLA4 antibody than wild-type tumor-bearing mice treated with each therapy alone or tumor-bearing mice that lack a functional ICOS pathway. (Image courtesy of James P. Allison)

Speaker:
Charles A. Dinarello, University of Colorado–Denver

Highlights

  • Blocking IL-1 using IL-1R antagonists or IL-1β antibodies can be beneficial not only against inflammatory diseases but also against diseases such as type 2 diabetes and cardiovascular disease, which are not considered inflammatory.
  • An anti-IL-1α antibody tested in a phase I trial in end-stage cancer patients with metastatic tumors showed efficacy by countering inflammation, leading to the reversal of weight loss in patients who responded to the therapy.

Role of interleukins in inflammatory diseases

Charles A. Dinarello of the University of Colorado–Denver pioneered the study of interleukin 1 (IL-1) in the pathogenesis and treatment of inflammatory diseases, first by establishing that a single cytokine could possess multiple biological properties and control the activity of different cell types in the innate and adaptive immune systems. On the 30th anniversary of his success cloning IL-1 and confirming it as the so-called fever molecule, he guided the audience through the key events in IL-1 research and explained how the molecule became an important therapeutic target in many inflammatory disease therapies.

An early experiment in the 1980s, in which humans injected with recombinant IL-1 displayed fever and related symptoms at low doses and hemodynamic shock at higher doses, ended the initial assumption that IL-1 could be used as an immunostimulant and prompted researchers to study the therapeutic benefit of blocking the cytokine.

The ensuing years saw an explosion of work on the basic biology of IL-1 signaling. Dinarello and others found that the IL-1 receptor, present on most cells, triggers intracellular signals through cytoplasmic Toll domains, recruiting the IRAK kinases to activate the transcription factor NF-kb. This factor turns on an array of cytokine and chemokine genes whose activation is associated with local and systemic inflammation that leads to tissue damage and remodeling and to organ failure.

IL-1 signaling activates an array of genes that control the activity of cytokines, chemokines, adhesion molecules, and inflammatory enzymes such as COX2. Thus the diverse benefits of blocking IL-1 signaling range from suppressing local inflammation to preventing tissue remodeling and destruction. (Image courtesy of Charles A. Dinarello)


 

IL-1 blockers find therapeutic success

Antagonism of the IL-1 receptor, which is expressed in most tissues, prevents binding of α and β isoforms of IL-1. There are many potential uses for IL-1-blocking therapy: in hereditary diseases with mutations that result in loss of control of IL-1 secretion, in chronic inflammatory diseases with no known genetic basis, and in common diseases like gout and type 2 diabetes that do not respond to therapies blocking other inflammatory cytokine such as TNF.

Anakinra, the recombinant form of the naturally occurring IL-1R antagonist (IL-1Ra) protein, was approved by the FDA in 2001 to treat RA. It has since proved efficacious in a broad array of diseases and is undergoing several clinical trials. Dinarello's group has shown that a single injection of anakinra ameliorates the symptoms of Still's disease, a rheumatic condition, in adults and children. The drug has also been shown in phase I trials to reverse developmental retardation associated with neonatal onset multisystem inflammatory disease and to reverse blindness in Behcet's disease.

Proof-of-concept studies have also demonstrated that blocking IL-1 activity with anakinra or anti-IL-1β antibodies could be a therapeutic strategy in diseases not considered inflammatory, such as type 2 diabetes and heart failure. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) trial is the largest randomized placebo-controlled trial designed in anti-cytokine therapeutics (n = ~10 000 patients). It is evaluating whether anti-IL-1β treatment reduces the risk of death from myocardial infarction, stroke, and cardiovascular disease in high-risk type 2 diabetes patients on statin therapy.

Inflammation is an important player in cancer, promoting angiogenesis, tumor invasiveness, metastasis, and cachexia (weight loss) by reducing appetite and increasing loss of muscle mass. Dinarello discussed the possibility of countering inflammation in cancer with an anti-IL-1α antibody. A recent phase I trial tested MABp1, a first-in-class human anti-IL-1α, in 52 patients with metastatic cancer of various types who had been through at least four lines of therapy and were considered to be end-stage. The trial showed a median survival benefit of 19.3 months in the 20 patients who were able to increase muscle mass in response to the drug.

Given the success of the IL-1-blocking approach across multiple diseases driven by inflammation, Dinarello expects that the list of indications for this drug and other anti-IL-1 agents will expand in the coming years.