Harnessing the Immune System: Introduction John C. Cambier, PhD Distinguished Professor and Chairman, Department of Immunology and Microbiology Director, Human Immunology and Immunology Initiative
1
Spectrum of Immunological Health rheumatoid arthritis autoimmune thyroid type 1 diabetes multiple sclerosis lupus
age-related macular degeneration (AMD)
Autoimmunity
type 2 diabetes obesity Metabolic syndrome cardiovascular aging disease
Inflammation
Human Immunology Initiative Clinical Care Delivery
acquired immunodeficiency failed immune syndrome (AIDS) surveillance of primary cancer immunodeficiency
Impairment
Perfect Balance Personalized Medicine Genetics
Deficiency
2
CU Immunological Health Initiative: Key Thought Leaders
Kathleen Barnes
Craig Jordan
John Cambier
Wells Messersmith
Thomas Flaig
Dennis Roop
Robert Fuhlbrigge
Lia Gore
Thomas Purcell
Clay Smith
Michael Holers
Michael Verneris
4
The Elephant in the Room: Cancer Immunotherapy 20 December 2013
Science magazine recognized Cancer Immunotherapy as the ‘Breakthrough of the Year’ in 2013 After decades of investigation the field of immunology has reached a critical inflection point; it has become possible to treat, and in many cases cure, diseases by interventions that target immunological functions
5
Cancer immunotherapies are treatments that act by improving the ability of the immune system to attack and destroy the tumor.
6
Most Exciting Cancer Immunotherapy Innovations CAR-T Cells – immune cells are removed from the patient’s blood and modified in the laboratory to help them fight cancer. These modified cells are then transfused back into the patient where they target and destroy cancer.
Checkpoint inhibitors – molecules that block the ability of cancer cells to evade the immune system, specifically prohibit the shut down ‘killer’ T cells. This allows the killer T cells to persist and attack the tumor.
7
CAR-T cells increased numbers of cells that target and destroy the tumor Normal (diverse) T cell repertoire
Modified (uniform) CAR-T cell repertoire
1/10,000 T cells attack the tumor (e.g. tumor cell antigen)
All T cells attack with the tumor
tumor
8
CAR-T cells Self-T cells are genetically modified to attack tumor cells T cells are isolated from the patient’s blood and genetically modified in the laboratory to express a receptor specific for an antigen expressed by the tumor cells The chimeric antigen receptor T cells (CAR-T cells) are then infused into the patient where they seek out and destroy the tumor.
tumor cell
T cell
modification : receptor specific for tumor cell antigen
modified 2012 American Association for Cancer Research
10
11
Scientists on the Anschutz Medical Campus Terry Fry, MD -
-
Recruited to CU AMC Feb 2018 from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) through collaboration between Children’s Hospital, CU and the Human Immunology and Immunotherapy Initiative Pediatrician that has successfully treated patients with CAR-T cells and runs a laboratory that studies ways in which to improve CAR-T cells
Enkhtsetseg ‘Enkhee’ Purev, MD, PhD -
Assistant Professor in the CU Blood Cancer and Bone Marrow Transplant (BMT) Program in the Division of Hematology in the CU School of Medicine Running a small clinical trial using CAR-T cells targeted at (CD19+) B cell leukemia Working with Clinimmune and the Gates Center (on the CU AMC) to produce clinically pure CAR-T cells on our campus for patient use
12
Most Exciting Cancer Immunotherapy Innovations CAR-T Cells – immune cells are removed from the patient’s blood and modified in the laboratory to help them fight cancer. These modified cells are then transfused back into the patient where they target and destroy cancer.
Checkpoint Blockade – molecules that block the ability of cancer cells to evade the immune system, specifically prohibit the shut-down of ‘killer’ T cells. This allows the killer T cells to persist and attack the tumor.
13
Checkpoint blockade: The Strategy tumor cell
T cell PD-1
PDL-1
Don’t kill me
STING-agonist tumor cell
PD-1
T cell
Kill !!!! Anti-PD-1 antibody
14
July 18, 2016
15
Scientists on the Anschutz Medical Campus William ‘Bill’ Robinson, MD, PhD • •
Professor of Medicine, Division of Medical Oncology Successfully treated numerous patients with checkpoint inhibitors for a variety of cancers, including melanoma
Wells Messersmith, MD • • •
Professor and Head, Division of Medical Oncology Program co-Leader, Developmental Therapeutics Associate Director for Translational Research
Fred Hirsch, MD, PhD •
•
Professor of Medicine and Pathology, Division of Medical Oncology, and the Pia and Fred R. Hirsch Endowed Chair for the University of Colorado Cancer Center Currently leading the “PD-L1 Blueprint Project,” which is supported by the FDA and is a collaboration with several pharmaceutical companies to analyze and compare all clinical PD-L1 assays
16
Cancer Immunotherapy: Not Without Risk
Checkpoint inhibitors may also remove the ‘brake’ from cells that are autoreactive and now able to destroy self tissue unchecked…
16
Spectrum of Immunological Health rheumatoid arthritis autoimmune thyroid type 1 diabetes multiple sclerosis lupus
age-related macular degeneration (AMD)
Autoimmunity
type 2 diabetes obesity Metabolic syndrome cardiovascular aging disease
Inflammation
acquired immunodeficiency failed immune syndrome (AIDS) surveillance of primary cancer immunodeficiency
Impairment
Deficiency
Checkpoint blockade therapy
Human Immunology Initiative Clinical Care Delivery
Perfect Balance Personalized Medicine Genetics
Questions and Answers: Pediatrics at the Forefront of Discovery Robert C. Fuhlbrigge, MD PhD Professor and Head, Pediatric Rheumatology President-elect of CARRA The Childhood Arthritis and Rheumatology Research Alliance
TRANSFORMING HEALTHCARE
Why Pediatrics? Pediatric patients with chronic inflammatory diseases are rare » Limited data to inform decisions
Concerns about efficacy and safety » Parents and Clinicians nervous about enrolling in blinded trials
Concerns about impact of disease and therapies on growth and development Limited workforce: <300 National, 6 Colorado/ Front range
TRANSFORMING HEALTHCARE
Why Pediatrics? Early-onset diseases reflects a genetically enriched population » Systemic Lupus – single gene disorders and multi-gene influences » Autoinflammatory diseases - IL-1β: From rare disease to common conditions
Pediatric patients have reduced complexity » Limited environmental exposures » Fewer comorbid conditions
Most pediatric rheumatic diseases have adult counterparts » Each field can inform the other
TRANSFORMING HEALTHCARE
21
22
TRANSFORMING HEALTHCARE
PATHOGENESIS OF SYSTEMIC LUPUS: DEFECTS IN ADAPTIVE IMMUNITY
Tsokos, G. C. et al. (2016)
TRANSFORMING HEALTHCARE
SINGLE-GENE MUTATIONS CAUSING SYSTEMIC LUPUS
23
24
TRANSFORMING HEALTHCARE
GENETIC ASSOCIATIONS IN SYSTEMIC LUPUS
Genetic Load Determines Risk In SLE
Langfield et al. Nature Communications. 8:16021, 2017
TRANSFORMING HEALTHCARE
GENETIC CORRELATES IN PEDIATRIC AND ADULT ARTHRITIS
SERONEGATIVE SEROPOSITIVE
SPONDYLOARTHRITIS
Early onset arthritis
Psoriatic JIA RF- Poly JIA
Psoriatic Arthritis
RF+ Poly JIA Seropositive RA
ERA
Oligo JIA
Seronegative RA
Systemic JIA Still’s Disease
SYSTEMIC Adapted from Nigrovic et al. Arthritis and Rheumatology 70:7-17 2018
TRANSFORMING HEALTHCARE
26
27
TRANSFORMING HEALTHCARE
AUTOINFLAMMATORY SYNDROMES
Cryopyrin-associated Periodic Syndromes (CAPS) Familial Cold Autoinflammatory Syndrome (FACS) » Cold induced fever, urticarial rash, arthralgia, conjunctivitis, <24 hours
Muckle-Wells Syndrome (MWS) » Intermittent fevers, urticarial rash, arthralgias, conjunctivitis » Progressive sensorineural hearing loss
Neonatal-onset Multisystem Inflammatory Disorder (NOMID) » Daily fever, urticarial rash, conjunctivitis, bony anomalies, growth failure » Sensorineural hearing loss
» Chronic aseptic meningitis, brain atrophy, early death
SEVERITY
TRANSFORMING HEALTHCARE
AUTOINFLAMMATORY SYNDROMES
Mutations in one protein (NALP3/ cryopyrin) cause FCAS, MWS and NOMID Induce activation of caspase-1, leading to overproduction of interleukin-1
TRANSFORMING HEALTHCARE
AUTOINFLAMMATORY SYNDROMES
Treatment of CAPS using IL-1 receptor antagonist Anakinra: A synthetic protein drug that blocks IL-1 binding to its receptor Immediate and highly effective control of symptoms in CAPS patients, including reversal of brain inflammation and growth failure in NOMID
30
TRANSFORMING HEALTHCARE
AUTOINFLAMMATORY SYNDROMES
NALP3/ Caspase-1 in Systemic-onset JIA Activation of the NALP3 inflammasome leads to production of IL-1 Overproduction of IL-1 leads to systemic features of systemic onset JIA Inhibition of IL-1 reverses these features
31
TRANSFORMING HEALTHCARE
AUTOINFLAMMATORY SYNDROMES
Interleukin-1 and Cardiovascular Disease Activation of the NALP3 inflammasome/ caspase-1 leads to production of IL-1 and IL-6 and increased C-reactive protein (CRP) Elevation of CRP is strongly associated with risk of CVD/ MI/ Stroke In a randomized, double blind trial of an anti-IL-1β antibody, patients receiving the drug experienced a 15% reduction in adverse cardiovascular events and reduced cancer mortality Proof-of-principle study: » Blocking IL-1 was equivalent to use of statins to prevent CVD » Other inhibitors of NALP3 pathway are now under study Ridker et al., N Engl J Med 2017; 377:1119-1131
TRANSFORMING HEALTHCARE
AUTOINFLAMMATORY SYNDROMES: SINGLE-GENE DEFECTS
TRANSFORMING HEALTHCARE
33
TRANSFORMING HEALTHCARE
CONCLUSIONS Although there are biologic differences between children and adults, most pediatric diseases share genetic and mechanistic features with adult counterparts Studying disease mechanisms in children has a number of advantages » Earlier-onset in general reflects a genetically enriched population, making it easier to identify genes of interest
» External influences and environmental exposure history are shorter and simpler- easier to identify and study enhancers and confounders
Collaboration between pediatric and adult investigators is the key to transforming healthcare in immune
35
TRANSFORMING HEALTHCARE
PEDIATRIC RHEUMATOLOGY
CARRA Research Network • • • •
Investigator led research network Founded 2002 120 sites, >500 members > 95% of all pediatric rheumatologists in North America • Research/ Research training • > $50 million in research funding to date • Highly collaborative structure
www.carragroup.org
36
TRANSFORMING HEALTHCARE
PEDIATRIC RHEUMATOLOGY
CARRA Research Portfolio Randomized multicenter clinical trials
Translational studies
Comparative Effectiveness Research
Pharmacosurveillance Program
Observational/Natural history studies
Sample Repository
Quality Improvement
CARRA Registry – foundation for studies
www.carragroup.org
Immune Modulation: Preventing Autoimmune Disease V. Michael Holers, MD Scoville Professor and Head, Division of Rheumatology PI of NIH-funded Colorado Autoimmune Center of Excellence & Colorado Autoimmune Disease Prevention Center
Autoimmune Diseases – Horror Autotoxicus Have Been Recognized for Over 125 Years
Stages of Pre-Clinical Autoimmunity and Transition to Clinical Disease RA
SLE Sjรถgren's
Scleroderma Type 1 Diabetes
Disease Classification
Stages of Pre-Clinical Autoimmunity and Transition to Clinical Disease RA
SLE Sjรถgren's
Scleroderma Type 1 Diabetes Genetic Predisposition (Healthy)
Disease Classification
SERA (Studies of the Etiology of Rheumatoid Arthritis) 2018 – Colorado Team
SERA: Studying the Factors that Drive the Initiation and Development of Seropositive RA
Genetic Risk [a]
Environmental Risk Factors [b]
Systemic Autoimmunity
Arthralgia
Unclassified Arthritis
Rheumatoid Arthritis
[c]
[d]
[e]
[f]
Preclinical RA Gerlag et al, Ann Rheum Dis 71:638-641, 2012
SERA: Studying the Factors that Drive the Initiation and Development of Seropositive RA Epidemiologic Factors: Smoking Hormones Stress Diet/Omega-3
Genetic Risk [a] Genetics: Risk Genes Gene Regulation
Environmental Risk Factors [b]
Immune Dysregulation: Autoantibodies Metabolomics Inflammatory Markers
Systemic Autoimmunity
Arthralgia
Unclassified Arthritis
Rheumatoid Arthritis
[c]
[d]
[e]
[f]
Mucosal Biology: Inflammation Local Autoantibodies Microbiome Changes
Preclinical RA Gerlag et al, Ann Rheum Dis 71:638-641, 2012
Robinson Lab Collaborations: Increasing Elevations in Blood ACPA and Cytokines as Approach Clinical RA Serial Pre-Clinical RA
Cytokines
Cit-antigens
>6 yrs
6–4 yrs 4-2 yrs 2-0 yrs
Serial Matched Controls RA
Colorado: “Mucosal-Initiation” Etiology in Pathogenesis of Early RA Inflammatory joint disease to classifiable RA
Initial generation of RArelated autoimmunity in mucosal sites through: - Loss of tolerance - Innate Immune activation - NET formation - Metabolomic changes
Other
Peripheral spread of autoimmune cells and autoantibodies to the spleen/lymph/bone marrow nodes and circulation (‘Preclinical RA’)
Colorado – Pre-Clinical RA Prevention in At-Risk Populations StopRA Strategy for the Prevention of Clinically-Apparent RA NIH-funded (NIAID/ACE) Kevin Deane and Michael Holers, Directors
CU – Pre-Clinical RA Prevention in At-Risk Populations
Genetic Risk
Environmental Risk Factors
Systemic Autoimmunity
Arthralgia
Unclassified Arthritis
[a]
[b]
[c]
[d]
[e]
Rheumatoid Arthritis
[f]
Gerlag et al, Ann Rheum Dis 71:638-641, 2012
CU – Pre-Clinical RA Prevention in At-Risk Populations PRAIRI Rituximab
Genetic Risk
Environmental Risk Factors
Systemic Autoimmunity
Arthralgia
Unclassified Arthritis
[a]
[b]
[c]
[d]
[e]
Rheumatoid Arthritis [f]
APIPPRA Abatacept STAPRA Statins
Gerlag et al, Ann Rheum Dis 71:638-641, 2012
CONCLUSIONS 1 Pioneering studies of autoimmune disease natural history are being performed and led at CU - Type 1 Diabetes (DAISY, TEDDY) - Celiac Disease (CEDAR) - Rheumatoid Arthritis (SERA) - Multiple Sclerosis (RisEMS)
2. These have promoted development of new field of Autoimmune Disease Prevention 3. Many challenges/opportunities are present - Screening needs to be expanded across diseases (100+) - Identification of novel therapeutic targets is underway - Clinical Trial designs need to be developed and integrated into industry
4. University of Colorado well-positioned to lead this area
Harnessing the Immune System: Cancer Treatment Wells Messersmith, MD, FACP Professor and Head, Division of Medical Oncology Associate Director for Translational Research, Cancer Center
51
OFFICE OF ADVANCEMENT
An Abbreviated History of Immunotherapy for Cancer 1890’s – Coley’s toxin’s >100 years of failed strategies
1970’s – BCG for bladder cancer 1992 – Interleukin-2 for melanoma and renal cell 1995 – Interferon a 2b for melanoma 2010 – Sipuleucel –T for prostate cancer 2011 – Ipilimumab (CTLA-4) for melanoma 2014 – Nivolumab and pembrolizumab (PD-1), melanoma
Checkpoint Inhibitors Taking the brake off the immune system Clinical Cancer Research
PD-1 blockade in Melanoma
Better response (tumor shrinkage) and survival. Less toxicity than cytotoxic (chemical) chemo. N Engl J Med. 2015
Does immunotherapy work for every cancer patient?
Can we use “personalized medicine� to find a subset?
Personalized Medicine Example: dMMR/MSI Colorectal Cancer • MMR = Mismatch repair proteins correct errors in DNA • MMR system tends to target alterations in short repeated DNA sequences (which have greater probability of error) Microsatellites Nature Reviews Immunology 2002
dMMR/MSI Tumors Have 20x more DNA mutations Mutation frequency in cancers
responders
Responses in MSI-H subgroup
Le, NEJM 2015
MSI-H tumor responses generally Broad range of tumor types! Le, Science 2017
Duration of Response: longer than typical Chemo This is the “value proposition� of immunotherapy: once the immune system is trained to kill the tumor, responses are long lasting. CURE?!!!
Small Percentages Add Up Endometrial (31.4%) MSI Colon (19.7%) Gastric AdenoCA (19.1%) Rectal (5.7%)
in 3.8% of all cancers ~66,000 in 2018
Esophageal (1.6%) Cholangiocarcinoma (1.4%) Hepatocellular (0.8%)
Bonneville, JCO Precision Oncology 2017
What if we use TWO immunotherapy drugs? PD-1 and CTLA-4
Response Rate=55% (compared to 34% with one drug)
What immunotherapy studies are going on at the University of Colorado? Institutional studies and industry collaborations
Targeting Immune Suppressor Cells with ATRA Martin McCarter, MD (Surgical Oncologist) -
Dr. McCarter has shown that ATRA decreases immune suppressor cells
-
He wrote a clinical trial, partially supported by a competitive NCI grant, combining ATRA with Ipilumumab in melanoma.
ATRA = All-Trans Retinoic Acid
PD-1, MEK, VEGF inhibition in colorectal cancer Chris Lieu, MD (Medical Oncologist) bevacizumab -
-
binimetinib pembolizumab
PD-1 inhibitors alone have not worked for (non dMMR) colorectal cancer; thus there is significant interest in combinations. MEK inhibitors have been shown to increase immune response. VEGF inhibitors also improve immune response. Dr. Lieu wrote a clinical trial, partially supported by industry collaborators, combining pembrolizumab (PD-1), binimetinib (MEK), and bevacizumab (VEGF).
Examples of “FIH” Collaborations with Industry 1. Bispecific monoclonal antibody (Roche): “Velcro” for immune cells and cancer cells (CU Leader: Chris Lieu, MD) 2. Live, Attenuated Double-Deleted Listeria (LADD; Arduro) with personalized tumor proteins (CU Leader: Wells Messersmith, MD) 3. STING (discovered by Cambier) immune pathway activator (CU Leader: Wells Messersmith, MD) 4. Liposomal mRNA for OX-40 checkpoint (CU Leader: Antonio Jimeno, MD/PhD) FIH = “first in human”
CONCLUSIONS 1 After decades of trying various strategies to harness the immune system against cancer, major advances have occurred: - “checkpoint� inhibitors (PD-1, PD-L1, CTLA-4). 2. Success of checkpoint inhibitor trials across multiple cancers: - melanoma, lung, head & neck, gastroesophageal, liver, colorectal, lymphoma, kidney, bladder, others 3. Despite progress, however, the vast majority of advanced cancer patients are not cured (1.7M cases, <600,000 deaths in 2018)
4. University of Colorado well-positioned to make break-throughs - very strong immunology science - numerous clinical trials (both industry and investigator-initiated)
Questions?
The Human Immunology Initiative John C. Cambier, PhD Distinguished Professor and Chairman, Department of Immunology and Microbiology Director, Human Immunology and Immunotherapy Initiative
1
Spectrum of Immunological Health rheumatoid arthritis autoimmune thyroid type 1 diabetes multiple sclerosis lupus
age-related macular degeneration (AMD)
Autoimmunity
type 2 diabetes obesity Metabolic syndrome cardiovascular aging disease
Inflammation
Human Immunology Initiative Clinical Care Delivery
acquired immunodeficiency failed immune syndrome (AIDS) surveillance of primary cancer immunodeficiency
Impairment
Perfect Balance Personalized Medicine Genetics
Deficiency
2
Human Immunology and Immunotherapy Initiative (HI3) The Human Immunology and Immunotherapy Initiative was founded in 2016 following successful competition for funding ($20M) from the Dean of University of Colorado School of Medicine. Its mission is to bring the Anschutz Medical Campus into international prominence in the area of human immunology and immunotherapy during the coming decade. To achieve this goal the HI3 will develop needed infrastructure, train future scientific leaders and recruit faculty to complement existing strengths.
3
Human Immunology and Immunotherapy Activities • Faculty Recruitment • Human Immune Monitoring Shared Resource • Translational Research Networking & Preclinical Models • Clinical Research Program • GMP Production of Immunotherapeutics • Training Program
4
HI3 Faculty Recruiting Mike Verneris, MD, from the University of Minnesota, arrived September 2016 Ron Schuyler, PhD, from the University of Colorado, arrived November 2017 Terry Fry, MD, from the National Cancer Institute, arrived January 2018
Paul Norman, PhD, from Stanford University, arrived March 2018 Erin Schenk, MD, from the Mayo Clinic, arrived May 2018 Tuoqi Wu, PhD, from the National Institutes of Allergy and Infectious Disease, to arrive January 2019
5
Human Immune Monitoring Shared Resource (HIMSR)
6
ucdenver.edu/HumanImmunology
Questions?